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Acknowledgments

The author and publisher of A First Course in Systems Biology, Second Edition
gratefully acknowledge the contributions of the following reviewers in the
development of this book:

Guy Grant, University of Bedfordshire

Princess Imoukhuede, University of Illinois at Urbana-Champaign
Dimitrios Morikis, University of California at Riverside
Oliver Schildgen, University of Witten
Manuel Simões, University of Porto
Mark Speck, Chaminade University
Marios Stavridis, Ninewells Hospital & Medical School
Geraint Thomas, University College London
Floyd Wittink, Leiden University
Contents

chapter 1: biological systems 1 3.2 Small-World Networks 58

Reductionism and Systems Biology 5 Dependencies Among Network
Even Simple Systems Can Confuse Us 8 Components 62
Why Now? 10 3.3 Causality Analysis 62
Communicating Systems Biology 13 3.4 Mutual Information 62
The Task Before Us 16 Bayesian Reconstruction of Interaction
Networks 63
Exercises 17
3.5 Application to Signaling Networks 66
References 17
3.6 Applications to Other Biological
Further Reading 18
Networks 69
Static Metabolic Networks and Their Analysis 69
chapter 2: Introduction to 3.7 Stoichiometric Networks 70
Mathematical Modeling 19 3.8 Variants of Stoichiometric Analysis 73
Goals, Inputs, and Initial Exploration 24 3.9 Metabolic Network Reconstruction 73
2.1 Questions of Scale 24 3.10 Metabolic Control Analysis 74
2.2 Data Availability 25 Exercises 78
Model Selection and Design 26 References 80
2.3 Model Structure 27 Further Reading 82
2.4 System Components 30
2.5 Model Equations 35
chapter 4: the Mathematics of
2.6 Parameter Estimation 36
biological systems 83
Model Analysis and Diagnosis 37
Discrete Linear Systems Models 85
2.7 Consistency and Robustness 38
4.1 Recursive Deterministic Models 85
2.8 Exploration and Validation of
4.2 Recursive Stochastic Models 88
Dynamical Features 40
Discrete Nonlinear Systems 91
Model Use and Applications 43
Continuous Linear Systems 93
2.9 Model Extensions and Refinements 43
4.3 Linear Differential Equations 94
2.10 Large-Scale Model Assessments 45
4.4 Linearized Models 95
2.11 Questions of Design 46
Continuous Nonlinear Systems 100
2.12 Simplicity versus Complexity 47
4.5 Ad hoc Models 101
Exercises 49
4.6 Canonical Models 102
References 50
4.7 More Complicated Dynamical
Further Reading 50
Systems Descriptions 110
Standard Analyses of Biological
chapter 3: static network Models 51 Systems Models 110
Strategies of Analysis 52 4.8 Steady-State Analysis 110
Interaction Graphs 53 4.9 Stability Analysis 115
3.1 Properties of Graphs 54 4.10 Parameter Sensitivity 118
 contents ix

4.11 Analysis of Systems Dynamics 119 6.13 Transcription Factors 188

Other Attractors 122 6.14 Models of Gene Regulation 190
4.12 Limit Cycles 123 Measuring Gene Expression 191
4.13 Chaotic Attractors 126 Localization of Gene Expression 194
Exercises 128 Outlook 196
References 132 Exercises 196
Further Reading 133 References 198
Further Reading 200

chapter 5: Parameter estimation 135

Parameter Estimation for Linear Systems 136 chapter 7: Protein systems 201
5.1 Linear Regression Involving a Chemical and Physical Features of Proteins 202
Single Variable 136 7.1 Experimental Protein Structure
5.2 Linear Regression Involving Several Determination and Visualization 206
Variables 138 An Incomplete Survey of the Roles and
Parameter Estimation for Nonlinear Systems 141 Functions of Proteins 208
5.3 Comprehensive Grid Search 143 7.2 Enzymes 209
5.4 Nonlinear Regression 145 7.3 Transporters and Carriers 211
5.5 Genetic Algorithms 146 7.4 Signaling and Messenger Proteins 214
5.6 Other Stochastic Algorithms 148 7.5 Proteins of the Immune System 215
5.7 Typical Challenges 149 7.6 Structure Proteins 216
Parameter Estimation for Systems of Current Challenges in Protein Research 218
Differential Equations 153 7.7 Proteomics 218
Structure Identification 160 7.8 Structure and Function Prediction 220
Exercises 161 7.9 Localization 222
References 166 7.10 Protein Activity and Dynamics 224
Further Reading 167 Exercises 226
References 228
Further Reading 230
chapter 6: Gene systems 169
The Central Dogma 169
chapter 8: Metabolic systems 231
Key Properties of DNA and RNA 171
Biochemical Reactions 232
6.1 Chemical and Physical Features 171
8.1 Background 232
6.2 Size and Organization of DNA 174
8.2 Mathematical Formulation of
6.3 Genes and Noncoding DNA 175 Elementary Reactions 234
6.4 Eukaryotic DNA Packing 178 8.3 Rate Laws 235
6.5 Epigenetics 178 Pathways and Pathway Systems 240
RNA 178 8.4 Biochemistry and Metabolomics 240
6.6 Messenger RNA (mRNA) 179 8.5 Resources for Computational
6.7 Transfer RNA (tRNA) 182 Pathway Analysis 241
6.8 Ribosomal RNA (rRNA) 182 8.6 Control of Pathway Systems 244
6.9 Small RNAs 183 Methods of Metabolomic Data Generation 246
6.10 RNA Viruses 184 8.7 Sampling, Extraction, and
Gene Regulation 185 Separation Methods 247
6.11 The lac Operon 186 8.8 Detection Methods 247
6.12 Modes of Regulation 187 8.9 Flux Analysis 249
x contents

From Data to Systems Models 250 chapter 11: Integrative Analysis of

8.10 Case Study 1: Analyzing Metabolism Genome, Protein, and
in an Incompletely Characterized Metabolite Data: A case
Organism 250 study in Yeast 303
8.11 Case Study 2: Metabolic Network On the Origin of Models 304
Analysis 251
A Brief Review of the Heat Stress
8.12 Case Study 3: Extraction of Dynamic Response in Yeast 306
Models from Experimental Data 251
11.1 The Trehalose Cycle 308
Exercises 252
Modeling Analysis of the Trehalose Cycle 310
References 254
11.2 Design and Diagnosis of a Metabolic
Further Reading 255 Pathway Model 310
11.3 Analysis of Heat Stress 312
chapter 9: signaling systems 257 11.4 Accounting for Glucose Dynamics 314
Static Models of Signal Transduction 11.5 Gene Expression 315
Networks 259 Multiscale Analysis 318
9.1 Boolean Networks 259 11.6 In Vivo NMR Profiles 318
9.2 Network Inference 261 11.7 Multiscale Model Design 320
Signal Transduction Systems Modeled with 11.8 The Trehalase Puzzle 324
Differential Equations 261 Concluding Comments 327
9.3 Bistability and Hysteresis 261 Exercises 328
9.4 Two-Component Signaling Systems 266 References 329
9.5 Mitogen-Activated Protein Kinase Further reading 330
Cascades 270
9.6 Adaptation 273
9.7 Other Signaling Systems 274 chapter 12: Physiological Modeling:
Exercises 278
the Heart as an example 331
Hierarchy of Scales and Modeling Approaches 332
References 279
12.1 Basics of Heart Anatomy 333
Further reading 281
12.2 Modeling Targets at the Organ Level 334
12.3 Modeling Targets at the Tissue Level 335
chapter 10: Population systems 283 12.4 Modeling Targets at the Cell Level 337
Population Growth 283
Simple Models of Oscillations 339
10.1 Traditional Models of
12.5 Black-Box Models of Oscillations 339
Population Growth 284
12.6 Summary of Black-Box Oscillation
10.2 More Complex Growth Phenomena 286
Models 342
Population Dynamics Under External
12.7 From a Black Box to Meaningful
Perturbations 288
Models 343
Analysis of Subpopulations 289
Electrochemistry in Cardiomyocytes 345
Interacting Populations 292
12.8 Biophysical Description of
10.3 General Modeling Strategy 292 Electrochemical Processes at the
10.4 Phase-Plane Analysis 292 Membrane of Cardiomyocytes 347
10.5 More Complex Models of 12.9 Resting Potentials and Action
Population Dynamics 297 Potentials 348
Exercises 299 12.10 Models of Action Potentials 350
References 301 12.11 Repeated Heartbeats 354
Further reading 302 Issues of a Failing Heart 355
 contents xi

12.12 Modeling Heart Function and Failure 14.3 Design Principles 404
Based on Molecular Events 356 14.4 Operating Principles 406
Outlook for Physiological Multiscale Goal-Oriented Manipulations and Synthetic
Modeling 361 Design of Biological Systems 407
Exercises 362 14.5 Metabolic Engineering 407
References 365 14.6 Synthetic Biology 408
Further Reading 366 Case Studies of Synthetic Biological
Systems Designs 411
chapter 13: systems biology in Medicine 14.7 Elementary Mode Analysis in
and Drug Development 369 Metabolic Engineering 411
Are you Unique? 369 14.8 Drug Development 414
13.1 Biological Variability and Disease 369 14.9 Gene Circuits 415
13.2 Modeling Variability and Disease 370 The Future Has Begun 419
Personalized Medicine and Predictive Health 372 Exercises 419
13.3 Data Needs and Biomarkers 373 References 421
13.4 Personalizing Mathematical Models 374 Further Reading 423
The Drug Development Process 378
The Role of Systems Biology in chapter 15: emerging topics in
Drug Development 380 systems biology 425
13.5 Computational Target and Lead Emerging Applications 426
Identification 381 15.1 From Neurons to Brains 426
13.6 Receptor Dynamics 382 15.2 Complex Diseases, Inflammation,
13.7 Pharmacokinetic Modeling 385 and Trauma 428
13.8 Pathway Screening with Dynamic 15.3 Organisms and their Interactions
Models 390 with the Environment 432
13.9 Emerging Roles of Systems Biology Modeling Needs 435
in Drug Development 393 15.4 Multiscale Modeling 436
Exercises 394 15.5 A Data-Modeling Pipeline 437
References 395 Toward a Theory of Biology . . . or Several
Further Reading 396 Theories? 439
References 441
chapter 14: Design of biological systems 399 Further Reading 443
Natural Design of Biological Systems 400
14.1 The Search for Structural Patterns 400 Glossary 445
14.2 Network Motifs 402 Index 459
Biological Systems
1
When you have read this chapter, you should be able to:
• Describe the generic features of biological systems
• Explain the goals of systems biology
• Identify the complementary roles of reductionism and systems biology
• List those challenges of systems biology that cannot be solved with intuition
alone
• Assemble a “to-do” list for the field of systems biology

When we think of biological systems, our minds may immediately wander to the
Amazon rainforest, brimming with thousands of plants and animals that live with
each other, compete with each other, and depend on each other. We might think of
the incredible expanse of the world’s oceans, of colorful fish swimming through
coral reefs, nibbling on algae. Two-meter-high African termite mounds may come
to mind, with their huge colonies of individuals that have their specific roles and
whose lives are controlled by an intricate social structure (Figure 1.1). We may think
of an algae-covered pond with tadpoles and minnows that are about to restart yet
another life cycle.
These examples are indeed beautiful manifestations of some of the fascinating
systems nature has evolved. However, we don’t have to look that far to find biologi-
cal systems. Much, much smaller systems are in our own bodies and even within our
cells. Kidneys are waste-disposal systems. Mitochondria are energy-production sys-
tems. Ribosomes are intracellular machines that make proteins from amino acids.
Bacteria are amazingly complicated biological systems. Viruses interact with cells in
a well-controlled, systemic way. Even seemingly modest tasks often involve an
amazingly large number of processes that form complicated control systems
(Figure 1.2). The more we learn about the most basic processes of life, such as cell
division or the production of a metabolite, the more we have to marvel the incredi-
ble complexity of the systems that facilitate these processes. In our daily lives, we
usually take these systems for granted and assume that they function adequately,
and it is only when, for example, disease strikes or algal blooms kill fish that we
realize how complex biology really is and how damaging the failure of just a single
component can be.
We and our ancestors have been aware of biological systems since the beginning
of human existence. Human birth, development, health, disease, and death have
long been recognized as interwoven with those of plants and animals, and with the
environment. For our forebears, securing food required an understanding of sea-
sonal changes in the ecological systems of their surroundings. Even the earliest for-
ays into agriculture depended on detailed concepts and ideas of when and what to
2 Chapter 1: Biological Systems

Figure 1.1 Biological systems abound at

all size scales. Here, a termite mound in
Namibia is visible evidence of a complex
social system. This system is part of a larger
ecological system, and it is at once the host
to many systems at smaller scales. (Courtesy
of Lothar Herzog under the Creative
Commons Attribution 2.0 Generic license.)

plant, how and where to plant it, how many seeds to eat or to save for sowing, and
when to expect returns on the investment. Several thousand years ago, the Egyp-
tians managed to ferment sugars to alcohol and used the mash to bake bread. Early
pharmaceutical treatments of diseases certainly contained a good dose of supersti-
tion, and we are no longer convinced that rubbing on the spit of a toad during full
moon will cure warts, but the beginnings of pharmaceutical science in antiquity and
the Middle Ages also demonstrate a growing recognition that particular plant prod-
ucts can have significant and specific effects on the well-being or malfunctioning of
the systems within the human body.
In spite of our long history of dealing with biological systems, our mastery of
engineered systems far outstrips our capability to manipulate biological systems.
We send spaceships successfully to faraway places and predict correctly when they
will arrive and where they will land. We build skyscrapers exceeding by hundreds of

ABA PEPC

RCN1

Sph SphK Malate

NOS Arg NlA12 Nitrite NADPH
S1P OST1

NO

GCR1 GPA1 AGB1

PLC PIP2 NAD+ ADPRc GTP GC InsPK Figure 1.2 Diagram of a complicated
PLD PC NADPH Atrboh
system of molecules that coordinate the
DAG InsP3 cADPR cGMP InsP6 RAC1 PA ROS response of plants to drought. While the
details are not important here, we can see
that a key hormone, called abscisic acid
CIS ABH1
ROP2 (ABA), triggers a cascade of reactions that
Actin ABI1 pHc ultimately promote the closure of stomata
and thereby reduce water evaporation [1].
ROP10 ERA1 CalM H+ ATPase
Even a narrowly defined response like this
Ca2+ ATPase closure process involves a complicated
Ca2+c KEV Depolar
control system that contains a multitude of
molecules and their interactions. In turn, this
AnionEM system is just one component within a much
KAP KOUT
larger, physiological stress response system
(cf. Figure 1.7). (From Saadatpour A, Albert I
& Albert A. J. Theor. Biol. 266 [2010] 641–656.
AtPP2C closure
With permission from Elsevier.)
 BIOLOGICAL SYSTEMS 3

times the sizes of the biggest animals and plants. Our airplanes are faster, bigger,
and more robust against turbulence than the most skillful birds. Yet, we cannot cre-
ate new human cells or tissues from basic building blocks and we are seldom able to
cure diseases except with rather primitive methods like cutting into the body or kill-
ing a lot of healthy tissue in the process, hoping that the body will heal itself after-
wards. We can anticipate that our grandchildren will only shake their heads at such
medieval-sounding, draconian measures. We have learned to create improved
microorganisms, for instance for the bulk production of industrial alcohol or the
generation of pure amino acids, but the methods for doing so rely on bacterial
machinery that we do not fully understand and on artificially induced random
mutations rather than targeted design strategies.
Before we discuss the roots of the many challenges associated with understand-
ing and manipulating biological systems in a targeted fashion, and our problems
predicting what biological systems will do under yet-untested conditions, we should
ask whether the goal of a deeper understanding of biological systems is even worth
the effort. The answer is a resounding “Yes!” In fact, it is impossible even to imagine
the potential and scope of advances that might develop from biological systems
analyses. Just as nobody during the eighteenth century could foresee the ramifica-
tions of the Industrial Revolution or of electricity, the Biological Revolution will
usher in an entirely new world with incredible possibilities. Applications that are
already emerging on the horizon are personalized medical treatments with minimal
side effects, pills that will let the body regain control over a tumor that has run amok,
prevention and treatment of neurodegenerative diseases, and the creation of spare
organs from reprogrammed stem cells. A better understanding of ecological systems
will yield pest- and drought-resistant food sources, as well as means for restoring
polluted soil and water. It will help us understand why certain species are threat-
ened and what could be done effectively to counteract their decline. Deeper insights
into aquatic systems will lead to cleaner water and sustainable fisheries. Repro-
grammed microbes or nonliving systems composed of biological components will
dominate the production of chemical compounds from prescription drugs to large-
scale industrial organics, and might create energy sources without equal. Modified
viruses will become standard means for supplying cells with healthy proteins or
replacement genes. The rewards of discovering and characterizing the general prin-
ciples and the specifics of biological systems will truly be unlimited.
If it is possible to engineer very sophisticated machines and to predict exactly
what they will do, why are biological systems so different and difficult? One crucial
difference is that we have full control over engineered systems, but not over biologi-
cal systems. As a society, we collectively know all details of all parts of engineered
machines, because we made them. We know their properties and functions, and we
can explain how and why some engineer put a machine together in a particular
fashion. Furthermore, most engineered systems are modular, with each module
being designed for a unique, specific task. While these modules interact with each
other, they seldom have multiple roles in different parts of the system, in contrast to
biology and medicine, where, for instance, the same lipids can be components of
membranes and have complicated signaling functions, and where diseases are
often not restricted to a single organ or tissue, but may affect the immune system
and lead to changes in blood pressure and blood chemistry that secondarily cause
kidney and heart problems. A chemical refinery looks overwhelmingly complicated
to a layperson, but for an industrial engineer, every piece has a specific, well-defined
role within the refinery, and every piece or module has properties that were opti-
mized for this role. Moreover, should something go wrong, the machines and facto-
ries will have been equipped with sensors and warning signals pinpointing problems
as soon as they arise and allowing corrective action.
In contrast to dealing with sophisticated, well-characterized engineered sys-
tems, the analysis of biological systems requires investigations in the opposite direc-
tion. This type of investigation resembles the task of looking at an unknown machine
and predicting what it does (Figure 1.3). Adding to this challenge, all scientists col-
lectively know only a fraction of the components of biological systems, and the spe-
cific roles and interactions between these components are often obscure and
change over time. Even more than engineered systems, biological systems are full of
sensors and signals that indicate smooth running or ensuing problems, but in most
4 Chapter 1: Biological Systems

Figure 1.3 Analyzing a biological system

resembles the task of determining the
function of a complicated machine
that we have never seen before. Shown
here as an example is the cesium fountain
laser table of the United States Naval
Observatory, which is used to measure time
with extreme accuracy. This atomic clock is
based on transitions in cesium, which have a
frequency of 9,192,631,770 Hz and are used
to define the second. See also [2].

cases our experiments cannot directly perceive and measure these signals and we
can only indirectly deduce their existence and function. We observe organisms,
cells, or intracellular structures as if from a large distance and must deduce from
rather coarse observations how they might function or why they fail.
What exactly is it that makes biological systems so difficult to grasp? It is cer-
tainly not just size. Figure 1.4 shows two networks. One shows the vast highway
system of the continental United States, which covers several million miles of major

(A)

Figure 1.4 The size of a network or

system is not necessarily correlated
with its complexity. (A) The network of
major highways in the continental United
States covers over 3 million square miles.
Nonetheless, its functionality is easy to
grasp, and problems with a particular road
are readily ameliorated with detours.
(B) The web of the European diadem spider
(Araneus diadematus) (C) is comparatively
small, but the functional details of this little
network are complex. Some lines are made
of silk proteins that have the tensile strength
of steel but can also be eaten and recycled
by the spider; other lines are adhesive due
to a multipurpose glue that may be sticky
(B) (C) or rubbery depending on the situation;
yet others are guide and signal lines that
allow the spider to move about and sense
prey. The creation of the web depends on
different types of spinneret glands, whose
development and function require the
complex molecular machinery of the spider,
and it is not yet clear how the instructions for
the complicated construction, repair, and use
of the web are encoded and inherited from
one generation to the next. ((A) From the
United States Department of Transportation.)
 REduCTIOnISM And SYSTEMS BIOLOGY 5

(A) Figure 1.5 Biological phenomena are often

difficult to understand, because our minds
are trained to think linearly. (A) The return
on an investment grows (or decreases) linearly
with the amount invested. (B) In biology, more
is not necessarily better. Biological responses
often scale within a modest range, but lead
to an entirely different response if the input is
× 100 increased a lot.

$100 investment $120 return $10,000 investment $12,000 return

(B)

× 100

1 tablespoon of fertilizer 50 blossoms 100 tablespoons of fertilizer dead roses!

highways. It is a very large system, but it is not difficult to understand its function or
malfunction: if a highway is blocked, it does not take much ingenuity to figure out
how to circumvent the obstacle. The other network is a comparably tiny system: the
web of a diadem spider. While we can observe the process and pattern with which
Ms. Spider spins her web, we do not know which neurons in her brain are respon-
sible for different phases of the complicated web production process and how she
is able to produce the right chemicals for the spider silk, which in itself is a marvel
of material science, let alone how she manages to survive, multiply, and maybe
even devour her husband.
Biological systems often consist of large numbers of components, but they pose
an additional, formidable challenge to any analysis, because the processes that
govern them are not linear. This is a problem, because we are trained to think in
linear ways: if an investment of $100 leads to a return of $120, then an investment of
$10,000 leads to a return of $12,000. Biology is different. If we fertilize our roses with
1 tablespoon of fertilizer and the rose bushes produce 50 blossoms, a little bit more
fertilizer may increase the number of blossoms, but 100 tablespoons of fertilizer will
not produce 5000 blossoms but almost certainly kill the plants (Figure 1.5). Just a
small amount of additional sun exposure turns a tan into sunburn. Now imagine
that thousands of components, many of which we do not know, respond in such a
fashion, where a small input does not evoke any response, more input evokes a
physiological response, and a little bit more input causes the component to fail or
exhibit a totally different “stress” response. We will return to this issue later in this
and other chapters with specific examples.

REduCTIOnISM And SYSTEMS BIOLOGY

So the situation is complicated. But because we humans are a curious species, our
forebears did not give up on biological analysis and instead did what was doable,
namely collecting information on whatever could be measured with the best current
methods (Figure 1.6). By now, this long-term effort has resulted in an amazing list of
biological parts and their roles. Initially, this list contained new plant and animal
6 Chapter 1: Biological Systems

Figure 1.6 Collecting information is the

first step in most systems analyses. The
eighteenth-century British explorer Captain
James Cook sailed the Pacific Ocean and
catalogued many plants and animal species
that had never been seen before in Europe.

species, along with descriptions of their leaves, berries, and roots, or their body
shapes, legs, and color patterns. These external descriptions were valuable, but did
not provide specific clues on how plants and animals function, why they live, and
why they die. Thus, the next logical step was to look inside—even if this required
stealing bodies from the cemetery under a full moon! Cutting bodies open revealed
an entirely new research frontier. What were all those distinct body parts and what
did they do? What were organs, muscles, and tendons composed of? Not surpris-
ingly, this line of investigation eventually led to the grand-challenge quest of discov-
ering and measuring all parts of a body, the parts of the parts (. . . of the parts), as well
as their roles in the normal physiology or pathology of cells, organs, and organisms.
The implicit assumption of this reductionist approach was that knowing the building
blocks of life would lead us to a comprehensive understanding of how life works.
If we fast-forward to the twenty-first century, have we succeeded and assembled
a complete parts catalog? Do we know the building blocks of life? The answer is a
combination of yes’s and no’s. The catalog is most certainly not complete, even for
relatively simple organisms. Yet, we have discovered and characterized genes, pro-
teins, and metabolites as the major building blocks. Scientists were jubilant when
the sequencing of the human genome in the early years of this millennium was
declared complete: we had identified the ultimate building blocks, our entire blue-
print. It turned out to consist of roughly three billion nucleotide pairs of DNA.
The sequencing of the human genome was without any doubt an incredible
achievement. Alas, there is much more to a human body than genes. So, the race for
building blocks extended to proteins and metabolites, toward individual gene varia-
tions and an assortment of molecules and processes affecting gene expression,
which changes in response to external and internal stimuli, during the day, and
throughout our lifetimes. As a direct consequence of these ongoing efforts, our parts
list continues to grow at a rapid pace: A parts catalog that started with a few organs
now contains over 20,000 human genes, many more genes from other organisms,
and hundreds of thousands of proteins and metabolites along with their variants. In
addition to merely looking at parts in isolation, we have begun to realize that most
biological components are affected and regulated by a variety of other components.
The expression of a gene may depend on several transcription factors, metabolites,
and a variety of small RNAs, as well as molecular, epigenetic attachments to its DNA
sequence. It is reasonable to expect that the list of processes within the body is much
larger than the number of components on our parts list. Biologists will not have to
worry about job security any time soon!
The large number of components and processes alone, however, is not the
only obstacle to understanding how cells and organisms function. After all, modern
computers can execute gazillions of operations within a second. Our billions of
telephones worldwide are functionally connected. We can make very accurate
 REduCTIOnISM And SYSTEMS BIOLOGY 7

predictions regarding a gas in a container, even if trillions of molecules are involved.

If we increase the pressure on the gas without changing the volume of the container,
we know that the temperature will rise, and we can predict by how much. Not so with
a cell or organism. What will happen to it if the environmental temperature goes up?
Nothing much may happen, the rise in temperature may trigger a host of physiologi-
cal response processes that compensate for the new conditions, or the organism may
die. The outcome depends on a variety of factors that collectively constitute a com-
plex stress response system (Figure 1.7). Of course, the comparison to a gas is not

H2O O2 ABIOTIC STRESS AND BIOTIC RESPONSES

PHOTOSYNTHESIS SA signaling JA signaling ET signaling
CO2

stomata SA JA ET

ETR1
NPR1 JAZ
EIN2
light ABA

photosynthesis WRKY MYC2 ERF

MVB DREB SA-responsive JA-responsive ET-responsive

genes genes genes

defence
Glu HXK1

AUX GA

ABA
CK

ethylene
pollinator

H2O CO
2
O2

light

VOC
ORGAN AND PLANT GROWTH
temperature
pathogens
AUX CK

nutrients, microbes CYCB

minerals KRP
water M
CDK
KEY:

transcription factors hormones CYCD

G2 G1 ANT

kinases carbohydrates CDKA

receptors enzymes S
CYCA DEL E2F RBR
other signaling proteins activation DP
CDKB CELL CYCLE
environmental interactions suppression

Figure 1.7 Stress responses are coordinated by systems at different levels of organization (cf. Figure 1.2). At the physiological level, the stress
response system in plants includes changes at the cellular, organ, and whole-plant levels and also affects interactions of the plant with other species.
(From Keurentjes JJB, Angenent GC, Dicke M, et al. Trends Plant Sci. 16 [2011] 183–190. With permission from Elsevier.)
8 Chapter 1: Biological Systems

quite fair, because, in addition to their large number, the components of a cell are not
all the same, which drastically complicates matters. Furthermore, as mentioned ear-
lier, the processes with which the components interact are nonlinear, and this per-
mits an enormous repertoire of distinctly different behaviors with which an organism
can respond to a perturbation.

EVEn SIMPLE SYSTEMS CAn COnFuSE uS

It is easy to demonstrate how quickly our intuition can be overwhelmed by a few E
nonlinearities within a system. As an example, let’s look at a simple chain of processes
and compare it with a slightly more complicated chain that includes regulation [3].
The simple case merely consists of a chain of reactions, which is fed by an external Input X Y Z
input (Figure 1.8). It does not really matter what X, Y, and Z represent, but, for the
sake of discussion, imagine a metabolic pathway such as glycolysis, where the input,
glucose, is converted into glucose 6-phosphate, fructose 1,6-bisphosphate, and pyru- Figure 1.8 The human brain handles
vate, which is used for other purposes that are not of interest here. For illustrative linear chains of causes and events very
well. In this simple pathway, an external
purposes, let’s explicitly account for an enzyme E that catalyzes the conversion of X input is converted sequentially into X, Y, and
into Y. Z, which leaves the system. The conversion of
We will learn in the following chapters how one can formulate a model of such a X into Y is catalyzed by an enzyme E. It is easy
pathway system as a set of differential equations. And while the details are not to imagine that any increase in Input will
important here, it does not hurt to show such a model, which might read cause the levels of X, Y, and Z to rise.

X = Input − aEX 0.5 ,

Y = aEX 0.5 − bY 0.5 , (1.1)
Z = bY 0.5 − cZ 0.5 .

Here, X, Y, and Z are concentrations, E is the enzyme activity, and a, b, and c are rate 1.0
constants that respectively represent how fast X is converted into Y, how fast Y is concentration X Z
converted into Z, and how quickly material from the metabolite pool Z leaves the Y
0.5
system. The dotted quantities on the left of the equal signs are differentials that
describe the change in each variable over time, but we need not worry about them
at this point. In fact, we hardly have to analyze these equations mathematically to 0
0 15 30
get an idea of what will happen if we change the input, because intuition tells us that time
any increase in Input should lead to a corresponding rise in the concentrations of
the intermediates X, Y, and Z, whereas a decrease in Input should result in smaller Figure 1.9 Simulations with the system
values of X, Y, and Z. The increases or decreases in X, Y, and Z will not necessarily be in (1.1) confirm our intuition: X, Y, and
exactly of the same extent as the change in Input, but the direction of the change Z reflect changes in Input. For instance,
should be the same. The mathematical solution of the system in (1.1) confirms this reducing Input in (1.1) to 75% at time
intuition. For instance, if we reduce Input from 1 to 0.75, the levels of X, Y, and Z 10 (arrow) leads to permanent decreases
decrease, one after another, from their initial value of 1 to 0.5625 (Figure 1.9). in X, Y, and Z.
Now suppose that Z is a signaling molecule, such as a hormone or a phospho-
lipid, that activates a transcription factor TF that facilitates the up-regulation of a
gene G that codes for the enzyme catalyzing the conversion of X into Y (Figure 1.10).
The simple linear pathway is now part of a functional loop. The organization of this
loop is easy to grasp, but what is its effect? Intuition might lead us to believe that the
positive-feedback loop should increase the level of enzyme E, which would result in E G TF
more Y, more Z, and even more E, which would result in even more Y and Z. Would
the concentrations in the system grow without end? Can we be sure about this pre-
diction? Would an unending expansion be reasonable? What will happen if we Input X Y Z
increase or decrease the input as before?
The overall answer will be surprising: the information given so far does not allow
us to predict particular responses with any degree of reliability. Instead, the answer Figure 1.10 Even simple systems may
depends on the numerical specifications of the system. This is bad news for the not allow us to make reliable predictions
unaided human mind, because we are simply not able to assess the numerical con- regarding their responses to stimuli.
Here, the linear pathway from Figure 1.8 is
sequences of slight changes in a system, even if we can easily grasp the logic of a
embedded into a functional loop consisting
system as in Figure 1.10. of a transcription factor TF and a gene G that
To get a feel for the system, one can compute a few examples with an expanded codes for enzyme E. As described in the text,
model that accounts for the new variables (for details, see [3]). Here, the results are the responses to changes in Input are no
more important than the technical details. If the effect of Z on TF is weak, the longer obvious.
 EVEn SIMPLE SYSTEMS CAn COnFuSE uS 9

response to a decrease in Input is essentially the same as in Figure 1.9. This is not too
surprising, because the systems in this case are very similar. However, if the effect of
Z on TF is stronger, the concentrations in the system start to oscillate, and after a
while these oscillations dampen away (Figure 1.11A). This behavior was not easy to
predict. Interestingly, if the effect is further increased, the system enters a stable
oscillation pattern that does not cease unless the system input is changed again
(Figure 1.11B).
The hand-waving explanation of these results is that the increased enzyme activ-
ity leads to a depletion of X. A reduced level of X leads to lower levels of Y and Z,
which in turn lead to a reduced effect on TF, G, and ultimately E. Depending on the
numerical characteristics, the ups and downs in X may not be noticeable, they may
be damped and disappear, or they may persist until another change is introduced.
Intriguingly, even if we know that these alternative responses are possible, the
unaided human mind is not equipped to integrate the numerical features of the
model in such a way that we can predict which system response will ensue for a
specific setting of parameters. A computational model, in contrast, reveals the
answer in a fraction of a second.
The specific details of the example are not as important as the take-home mes-
sage: If a system contains regulatory signals that form functional loops, we can no
longer rely on our intuition for making reliable predictions. Alas, essentially all real-
istic systems in biology are regulated—and not just with one, but with many control
loops. This leads to the direct and sobering deduction that intuition is not sufficient
and that we instead need to utilize computational models to figure out how even
small systems work and why they might show distinctly different responses or even
fail, depending on the conditions under which they operate.
The previous sections have taught us that biological systems contain large num-
bers of different types of components that interact in potentially complicated ways
and are controlled by regulatory signals. What else is special about biological sys-
tems? Many answers could be given, some of which are discussed throughout this
book. For instance, two biological components are seldom 100% the same. They vary
from one organism to the next and change over time. Sometimes these variations are
inconsequential, at other times they lead to early aging and disease. In fact, most

(A)
2

X
concentration

TF, E, G

Z
Y

0
0 50 100
time
(B)
5.0

Figure 1.11 Simulation results

X demonstrate that the looped system
in Figure 1.10 may exhibit drastically
concentration

different responses. If the effect of Z on TF

2.5 is very small, the response is essentially like
that in Figure 1.9 (results not shown). (A) If
Y, Z, the effect of Z on TF is relatively small, the
TF, E, functional feedback loop causes the system
G
to go through damped oscillations before
0 assuming a new stable state. (B) For stronger
0 250 500 2000 2250 2500 effects of Z on TF, the system response is a
time persistent oscillation.
10 Chapter 1: Biological Systems

diseases do not have a single cause, but are the consequence of an unfortunate com-
bination of slight alterations in many components. Another feature that complicates
intuition is the delay in many responses to stimuli. Such delays may be of the order of
seconds, hours, or years, but they require the analyst to study not merely the present
state of a biological system but also its history. For instance, recovery from a severe
infection depends greatly on the preconditioning of the organism, which is the col-
lective result of earlier infections and the body’s responses [4].
Finally, it should be mentioned that different parts of biological systems may
simultaneously operate at different scales, with respect to both time and space.
These scales make some aspects of their analysis easier and some harder. Let’s begin
with the temporal scale. We know that biology at the most basic level is governed by
physical and chemical processes. These occur on timescales of the order of millisec-
onds, if not faster. Biochemical processes usually run on a scale of seconds to min-
utes. Under favorable conditions, bacteria divide every 20–30 minutes. Our human
lifespan extends to maybe 120 years, evolution can happen at the genetic level with
lightning speed, for instance, when radiation causes a mutation, while the emer-
gence of an entirely new species may take thousands or even millions of years. On
one hand, the drastically different timescales make analyses complicated, because
we simply cannot account for rapid changes in all molecules of an organism over an
extended period of time. As an example, it is impossible to study aging by monitor-
ing an organism’s molecular state every second or minute. On the other hand, the
differences in timescales justify a very valuable modeling “trick” [5, Chapter 5]. If we
are interested in understanding some biochemical process, such as the generation
of energy in the form of adenosine triphosphate (ATP) by means of the conversion
of glucose into pyruvate, we can assume that developmental and evolutionary
changes are so slow in comparison that they do not change during ATP production.
Similarly, if we study the phylogenetic family tree of species, the biochemical pro-
cesses in an individual organism are comparatively so fast that their details become
irrelevant. Thus, by focusing on just the most relevant timescale and ignoring much
faster and much slower processes, any modeling effort is dramatically simplified.
Biology also happens on many spatial scales. All processes have a molecular
component, and their size scale is therefore of the order of ångströms and nanome-
ters. If we consider a cell as the basic unit of life, we are dealing with a spatial scale
of micrometers to millimeters, with some exceptions such as cotton “fiber” cells
reaching the length of a few centimeters [6] and the afferent axons of nerve cells in
giraffes, reaching from toe to neck, extending to 5 meters [7, p. 14]. The sizes of typi-
cal cells are dwarfed by higher plants and animals and by ecosystems such as our
oceans, which may cover thousands of square kilometers. As with the different tem-
poral scales, and using analogous arguments, models of biological systems often
focus on one or two spatial scales at a time [5]. Nonetheless, such simplifications are
not always applicable, and some processes, such as aging and algal blooms, may
require the simultaneous consideration of several temporal and spatial scales. Such
multiscale assessments are often very complicated and constitute a challenging
frontier of current research (see Chapter 15).

WHY nOW?
Many of the features of biological systems have been known for quite a while, and,
similarly, many concepts and methods of systems biology have their roots in its
well-established parent disciplines, including physiology, molecular biology, bio-
chemistry, mathematics, engineering, and computer science [8–11]. In fact, it has
been suggested that the nineteenth-century scientist Claude Bernard might be con-
sidered the first systems biologist, since he proclaimed that the “application of
mathematics to natural phenomena is the aim of all science, because the expression
of the laws of phenomena should always be mathematical” [12, 13]. A century later,
Ludwig von Bertalanffy reviewed in a book his three decades of attempting to con-
vince biologists of the systemic nature of living organisms [14, 15]. At the same time,
Mihajlo Mesarović used the term “Systems Biology” and declared that “real
advance . . . will come about only when biologists start asking questions which are
based on systems-theoretic concepts” [16]. The same year, a book review in Science
 WHY nOW? 11

envisioned “. . . a field of systems biology with its own identity and in its own right”
[17]. A few years later, Michael Savageau proposed an agenda for studying biologi-
cal systems with mathematical and computational means [5].
In spite of these efforts, systems biology did not enter the mainstream for several
more decades. Biology kept its distance from mathematics, computer science, and
engineering, primarily because biological phenomena were seen as too complicated
for rigorous mathematical analysis and mathematics was considered applicable only
to very small systems of little biological relevance. The engineering of biological sys-
tems from scratch was impossible, and the budding field of computer science con-
tributed to biology not much more than rudimentary data management.
So, why has systems biology all of the sudden moved to the fore? Any good detec-
tive will know the answer: motive and opportunity. The motive lies in the realization
that reductionist thinking and experimentation alone are not sufficient if complex
systems are involved. Reductionist experiments are very good in generating detailed
information regarding specific components or processes of a system, but they often
lack the ability to characterize, explain, or predict emergent properties that cannot
be found in the parts of the system but only in their web of interactions. For instance,
the emergence of oscillations in the example system represented by the equations
in (1.1) cannot be credited to a single component of the system but is a function of
its overall organization. Although we had complete knowledge of all details of the
model pathway, it was very difficult to foresee its capacity either to saturate or oscil-
late in a damped or stable fashion. Biology is full of such examples.
A few years ago, Hirotada Mori’s laboratory completed the assembly of a com-
plete catalogue of single mutants in the bacterium Escherichia coli [18]. Yet, the
scientific community is still not able to foresee which genes the bacterium will up-
or down-regulate in response to new environmental conditions. Another very chal-
lenging example of emergent system properties is the central nervous system. Even
though we understand quite well how action potentials are generated and propa-
gated in individual neurons, we do not know how information flows, how memory
works, and how diseases affect the normal functioning of the brain. It is not even
clear how information in the brain is represented (see also Chapter 15). Thus, while
reductionist biology has been extremely successful and will without any doubt
continue to be the major driving force for future discovery, many biologists have
come to recognize that the detailed pieces of information resulting from this
approach need to be complemented with new methods of system integration and
reconstruction [19].
The opportunity for systems biology is the result of the recent confluence and
synergism of three scientific frontiers. The first is of course the rapid and vast accu-
mulation of detailed biological information at the physiological, cellular, molecular,
and submolecular levels. These targeted investigations of specific phenomena are
accompanied by large-scale, high-throughput studies that were entirely infeasible
just a couple of decades ago. They include quantification of genome-wide expres-
sion patterns, simultaneous identification of large arrays of expressed proteins,
comprehensive profiling of cellular metabolites, characterization of networks of
molecular interactions, global assessments of immune systems, and functional
scans of nervous systems and the human brain. These exciting techniques are gen-
erating unprecedented amounts of high-quality data that are awaiting systemic
interpretation and integration (Figure 1.12).
The second frontier is the result of ingenuity and innovation in engineering,
chemistry, and material sciences, which have begun to provide us with a growing
array of technologies for probing, sensing, imaging, and measuring biological sys-
tems that are at once very detailed, extremely specific, and usable in vivo. Many
tools supporting these methods are in the process of being miniaturized, in some
cases down to the nanoscale of molecules, which allows diagnoses with minute
amounts of biological materials and one day maybe biopsies of individual, living
cells. Devices at this scale will allow the insertion of sensing and disease treatment
devices into the human body in an essentially noninvasive and harmless fashion
[20–22]. Bioengineering and robotics are beginning to render it possible to measure
hundreds or thousands of biomarkers from a single drop of blood. It is even becom-
ing feasible to use molecular structures, prefabricated by nature, for new purposes
in medicine, drug delivery, and biotechnology (Figure 1.13).
12 Chapter 1: Biological Systems

short-day long-day Figure 1.12 Modern high-throughput

methods of molecular biology offer data
1st 2nd 1st 2nd
in unprecedented quantity and quality.
0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20 0 4 8 12 16 20 As an example, the heat map shown here
represents a genome-wide expression
profile of 24-hour-rhythmic genes in the
mouse under chronic short-day (left two
panels) and long-day (right two panels)
conditions. (From Masumoto KM, Ukai-
Tadenuma M, Kasukawa T, et al. Curr. Biol.
20 [2010] 2199–2206. With permission from
Elsevier.)
24 h rhythmic genes

–2SD 0 +2SD

The third frontier is the co-evolution of mathematical, physical, and computa-

tional techniques that are more powerful and accessible to a much wider audience
than ever before. Imagine that only a few decades ago computer scientists used
punch cards that were read by optical card readers (Figure 1.14)! Now, there are
even specific computing environments, including Mathematica• and MATLAB•, as
well as different types of customized mark-up languages (XML), such as the systems
biology mark-up language SBML [23] and the mark-up language AGML, which was
developed specifically for analyzing two-dimensional gels in proteomics [24].
Before today’s much more effective computer science techniques were avail-
able, it was not even possible to keep track of the many components of biological
systems, let alone analyze them. But over the past few decades, a solid theoretical
and numerical foundation has been established for computational methods specifi-
cally tailored for the investigation of dynamic and adaptive systems in biology and
medicine. These techniques are now at the verge of making it possible to represent
and analyze large, organizationally complex systems and to study their emergent
properties in a rigorous fashion. Methods of machine learning, numerical mathe-
matics, and bioinformatics permit the efficient mining and analysis of the most use-
ful data from within an overwhelming amount of data that are not pertinent for
a given task. Algorithmic advances permit the simulation and optimization of
very large biological flux distribution networks. Computer-aided approximation
approaches yield ever-finer insights into the dynamics of complex nonlinear sys-
tems, such as the control of blood flow in healthy and diseased hearts. New mathe-
matical, physical, and computational methods are beginning to make it possible to
Exploring the Variety of Random
Documents with Different Content
extempore prayers—almost the only ones I have ever heard in which
there was nothing offensive—he began his sermon on a text in
Ecclesiastes. As it had little bearing on the argument, and was never
alluded to again, I do not repeat it.
“There is much talk,” M. Revel began, “in our day about an order
of nature. All acknowledge it; as science advances it is found more
and more to be unchangeable. We ought to rejoice in this
unchangeableness of the order of nature, for it is a proof of the
existence of a God of order. Had we found the earth all in confusion
it would have been a proof that there could be no such God. But this
God has established a moral order for man as unchangeable as the
order of nature. It was recognised by the heathen who worshipped
Nemesis. The whole of history is one long witness to this moral
order, but we need not go back far for examples. Look at Poland,
partitioned by three great monarchs, and at what is happening and
will happen there. Look at America, the land of equality, of freedom,
of boundless plenty, and what has come on her for the one great sin
of slavery. Look at home, at the story of the great man who ruled
France at the beginning of our new era, the man of success—‘qui
éblouissait lui-même en éblouissant les autres,’ who answered by
victory upon victory those who maintained that principle had still
something to say to the government of the world, and remember his
end on the rock in mid-ocean.
“Be sure, then, that there is an unchangeable moral order, and
this is the first law of it, ‘Qui fait du mal fait du malheur.’ The most
noticeable fact in connection with this moral order which our time is
bringing out is the solidarité of the human race. The solidarité of the
family and the nation was recognised in old times. Now, commerce
and intercourse are breaking down the barriers of nations. A
rebellion in China, a war in America, is felt at once in France, and
the full truth is dawning upon us that nothing but a universal
brotherhood will satisfy men. But you may say that punishment
follows misdoing so slowly that the moral order is virtually set aside.
Do not believe it. ‘Qui fait du mal fait du malheur.’ The law is certain;
but if punishment followed at once, and fully, on misdoing, mankind
would be degraded. On the other hand, ‘Qui fait du bon fait du
bonheur,’ and this law is equally fixed and unchangeable in the
moral order of the world.
“You may wonder that I have scarcely used the name of Christ to
you to-day; but what need? I have spoken of humanity; He is the
Son of Man, of a universal brotherhood which has no existence
without Him, of which He is the founder and the head.”
As we came out of church it was amusing to hear the comments
of the audience, at least of the English portion. Some called it rank
Socialism, others paganism, others good sound Christian teaching;
but all seemed to agree that it was very stirring stuff, and that this
would be the last time that M. Bevel would be allowed to address his
old fellow-townsmen from the pulpit. Indeed, his sketch of Napoleon
I. was much too true to be acceptable to Napoleon III., and though
his doctrine of universal brotherhood may be overlooked, I should
scarcely think that his historical views can be. I was utterly
astonished myself to hear such a sermon in a French pulpit. I had
never heard M. Bevel before; but his reputation, which seems to be
very great, is thoroughly deserved. The sermon of which I have tried
to give you a skeleton lasted for fifty minutes, and never flagged for
a moment. Sometimes he was familiar and colloquial, sometimes
impassioned, sometimes argumentative, but always eloquent. He
spoke with his whole body as well as with his voice, which last organ
was managed with rare skill; and, indeed, every faculty of the man
was thoroughly trained for his work, and so well trained, that
notwithstanding my English dislike to action or oratory in a pulpit, I
never felt that it was overdone or in bad taste. In short, I never
heard such scientific preaching, and came away disabused of the
notion that extempore sermons must be either flat, or vulgar, or
insincere. I only wish our young parsons would take the same pains
in cultivating their natural gifts as M. Revel has done, and hope that
any of them who may chance to read this will take an opportunity
the next time they are at Amsterdam of going to hear M. Revel, and
taking a lesson. I have been trying to satisfy myself for the last three
days what it is which makes this town so wonderfully different from
any English provincial town of the same size. I do not mean the
watering-place end of it next the sea, which is composed of the
crystal palace known as the établissement des bains, great hotels,
and expensive lodging-houses,—this quarter is inhabited by
strangers of all nations, and should be compared to Brighton or
Scarborough,—but the quiet old town behind, which has nothing in
common with the watering-place, and is as hum-drum a place as
Peterborough. As far as I can make out, the difference lies in the
enjoyment which these Dieppois seem to take in their daily business.
We are called a nation of shopkeepers now by all the world, so I
suppose there must be some truth in the nickname. But certainly the
Englishman does his shopkeeping with a very bad grace, and not the
least as if he liked it. He sits or stands at his counter with grim,
anxious face, and it requires an effort, after one has entered his trap
and asked a question as to any article, to retire without buying. The
moment his closing time comes, up go the shutters, and he clears
out of the shop, and takes himself off out of sight and hearing of it
as fast as he can. But here in Dieppe (and the rule holds good, I
think, in all French towns) the people seem really to delight in their
shops, and by preference to live in them, and in the slice of street in
front of them, rather than in any other place. In fact, the shops
seem to be convenient places opened to enable their owners to
causer with the greatest possible number of their neighbours and
other people, rather than places for the receipt of custom and
serious making of money. I doubt if any man is a worse hand at
shopping than I, and yet I can go boldly into any shop here, and
turn over the articles, and chaffer over them, and then go out
without buying, and yet feel that I have conferred a benefit rather
than otherwise on the proprietor of the establishment. And as to
closing time, there is no such thing. The only difference seems to be
that after a certain hour, if you choose to walk into a shop, you will
probably find yourself in a family party. No one turns off the gas until
he goes to bed, so as you loiter along you have the advantage of
seeing everything that is going on, and the inhabitants have what
they clearly hold to be an equivalent, the opportunity of looking at
and talking about you. The master of the shop sits at his ease,
sometimes reading his journal, sometimes still working at his trade
in an easygoing way, as if it were a pleasure to him, and chatting
away as he works. His wife is either working with her needle or
casting up the accounts of the day, but in either case is ready in a
moment to look up and join in any talk that may be going on. The
younger branches of the family disport themselves on the floor, or
play dominoes on the counter, or flirt with some neighbour of the
opposite sex who has dropped in, in the further corners. The
pastrycooks’ seem favourite social haunts, and often you will find
two or three of the nearest shops deserted, and the inmates
gathered in a knot round the sleek, neatly-shaved citizens who
preside in spotless white caps, jackets, and aprons, over these
temples of good things. In short, the life of the Dieppe burgher is
not cut into sharp lengths as it would be with us, one of which is
religiously set apart for trade and nothing else. Business and
pleasure seem with him to be run together, and he surrounds the
whole with a halo of small-talk which seems to make life run off
wonderfully easily and happily to him. Whether his method of
carrying on trade results in as good articles as with us I cannot say,
for the Dieppois is by no means guileless enough to part with his
wares cheap, so that I have had very little experience of them. But
certainly the general aspect of his daily life, so much more easy, so
much more social than that of his compeer in England, has a good
deal of fascination about it. On better acquaintance very possibly the
charm might disappear, but at first one is inclined strongly to wish
that we could take a leaf out of his book, and learn to take things
more easily. The wisdom which has learnt that there are vastly few
things in this world worth worrying about will, I fear, be a long time
in leavening the British nation.
The people of Dieppe are a remarkably well-conducted and
discreet folk in every way—wonderfully so when one considers their
close neighbourhood to the richest and most fashionable crowd
which frequents any French watering-place. Of these, and their
amusements, and habits, and wonderful costumes in and out of the
sea, I have no room to speak in this letter. They are now gone, or
fast going, and this is the time for people of moderate means and
quiet tastes, who wish to enjoy the deliciously exciting air and pretty
scenery of this very charming old sea town, which furnished most of
the ships for the invasion of England eight hundred years ago, and
will well repay the costs of a counter invasion. Only let the English
invader take care when he sets his foot on the Norman shore, unless
he thinks it worth while to be fleeced for the honour and glory of
being under the same roof with French dukes, Russian princes, and
English milords, to give a wide berth to the Hotel Royal. I am happy
to say I do not speak from personal experience, but only give voice
to the universal outcry against the extortion of this huge hotel, the
most fashionable in Dieppe. The last story is that an English
nobleman travelling with a courier, who arrived late one evening, did
not dine, and left early the next morning, had to pay a bill of 75
francs for his entertainment. The bill must have been a work of-high
art.
I hope in another letter to give you some notions of the watering-
place life, which is very quaint and amusing, and as unlike our
seaside doings as the old town is unlike our ordinary towns.
 Bathing at Dieppe, 17th September
1863.

T
hat great work, the Sartor Resartus, should have contained a
chapter on bathing-dresses, and I have no doubt would have
done so had the author been a frequenter of French watering-
places. Each of these—even such a little place as Treport—has its
établissement des bains, its etiquettes and rules as to the dress and
comportment of its bathing populations; and Dieppe is the largest,
and not the least quaint, of them all. The établissement here is a
long glass and iron building like the Crystal Palace, with a dome in
the middle, under which there are daily concerts and nightly balls;
and a transept at each end, one of which is a very good reading-
room, while in the other a mild kind of gambling goes on, under the
form of a lottery, for smelling bottles, clocks, and such like ware. I
am told that the play here is by no means so innocent as it looks,
and that persons in search of investments for spare cash can be
accommodated to any amount, but to a stranger nothing of this
discloses itself. Between this building and the sea there runs a
handsome esplanade, the favourite promenade, and immediately
underneath are the rows of little portable canvas huts which serve as
bathing machines. The ladies bathe under one end of the esplanade,
and the gentlemen under the other, while the fashionable crowd
leans over, or sits by the low esplanade wall, inspecting the
proceedings. This contiguity is, no doubt, the cause of the wonderful
toilets, spécialités des bains, which fill the shops here, and are used
by all the ladies and many of the men. They consist of large loose
trousers and a jacket with skirts, made of fine flannel or serge, of all
shades of colour according to taste, and of waterproof bathing caps,
all of which garments are trimmed with blue, or pink, or red bows
and streamers. Over all the baigneurs comme il faut throw a large
cloak, also tastefully trimmed. Thus habited the lady walks out of her
hut attended by a maid, to whom when she reaches the water’s
edge she hands her cloak, and, taking the hand of one of the male
baigneurs, proceeds with such plunges and dancings as she has a
fancy for, and then returns to the shore, is enveloped in her cloak by
her maid, and re-enters her hut. These male baigneurs are a
necessary accompaniment of the performance. I have only heard of
one case of resistance to the custom, which ended comically
enough. A young Englishman, well known in foreign society, was
here with his wife, who insisted on bathing, but vowed she would go
into the water with no man but her husband. He consented, and in
due course appeared on the ladies’ side with his pretty wife, in most
discreet apparel, went through the office of baigneur, and returned
to his own side. This raised a storm among the lady bathers, and the
authorities interfered. The next day the lady went to the gentlemen’s
side; but this was even more scandalous, and was also forbidden.
The persecuted couple then took; to bathing at six in the morning;
but, alas! on the second morning the esplanade was lined even at
that untimely hour by young Frenchmen, who, though by no means
early risers, had made a point of being out to assist at the bath of
their eccentric friends, and as these last did not appreciate the éclat
of performing alone for the amusement of their friends, the lawless
efforts of ces Anglais came to an end. In England, where dress for
the water is not properly attended to by either sex, one quite
understands the rule of absolute separation; but here, where every
lady is accompanied by a man in any case, where she is more
covered than she is in a ballroom, and where all her acquaintance
are looking on, it does not occur to one why she should not be
accompanied by her husband. For, as on the land, here people are
much better known by their dress in the water than by anything
else. A young gentleman asked one of his partners whether she had
seen him doing some particular feat of swimming that morning; she
answered that she had not recognised him, to which he replied, “Oh!
you may always know me by my straw hat and red ribbon.” The
separation here is certainly a farce, for at sixty yards, as we know
from our musketry instructors, you recognise the features of the
party; and the distance between the men and women bathers is not
so much. The rule is enforced, however, at any depth. A brother and
sister, both good swimmers, used to swim out and meet one another
at the boat which lies in the offing in case of accidents. But this was
stopped, as they talked together in English, which excited doubts as
to their relationship. I suppose it would be more improper for girls
and boys of marriageable age to swim together than to walk; but I
vow at this moment I cannot see why.
You may fancy, sir, that in such a state of things as I have
described, good stories on the great bathing subject are rife. The
last relates to a beauty of European celebrity, who is known to be
here and to be bathing, but keeps herself in such strict privacy that
scarcely a soul has been able to get a look at her, even behind two
thick veils. Had she really wished to be unnoticed she could not have
managed worse. The mystery set all the female world which
frequents the établissement in a tremor. They were like a knot of
sportsmen when a stag of ten tines has been seen in the next glen,
or when a 30 lb. salmon has broken the tackle of some cunning
fisherman, and is known to lie below a certain stone. Of course, they
were sure that something dreadful must have happened to her
looks, which she who should be happy enough to catch her bathing
would detect. In spite of all, the beauty eluded them for some time,
but at last she has been stalked, and I am proud to say, sir, by a
sportswoman of our own country. By chance this lady was walking at
eight in the morning, when the tide was so low that no one was
bathing. She saw a figure dressed en bourgeoise approaching the
bathing-place, apparently alone, but two women suspiciously like
maids followed at a respectful distance. It flashed across our
countrywoman that this must be the incognita; she followed. To her
delight, the three turned to the bathing-ground, and disappeared in
two huts which had been placed together apparently by accident.
She took up a position a few yards from the huts. After an agonising
pause the door opened, and a head appeared, which was instantly
withdrawn, but now too late. The mystery was solved. It was too
late-to send maids to the directeur of the baths to warn off the
spectator, and, moreover, useless, for she politely declined to move,
though there was nothing more to discover. The whole
establishment is ringing with the news that the beauty is pale
comme une morte, and the inference, of course, follows that paint
has been forbidden. You will also, sir, no doubt, be interested to
know that she wears a red rose on the top of her bathing-cap,
which, having regard to her present complexion, does not say much
for her taste in the choice of colours.
But if the water toilets here are fabulous, what shall I say of those
on the land? The colours, the textures, the infinite variety, and
general loudness of these bewilder the sight and baffle the pen of
ordinary mortals. The keenest rivalry is kept up amongst the fair
frequenters of the establishment. They sit by hundreds there
working and casing of afternoons, while the band plays from three
to six, or sweeping about on the esplanade; and in the evening are
there again in ever new and brighter colours. The Dieppe Journal
comments on the most striking toilets. It noticed with commendation
the purple velvet petticoats of the ladies of a millionaire house; it
glowed in describing the “toilette Écossaise” of another rich
Frenchwoman. An officer on reading the announcement laid down
the paper, and addressed a lady, his neighbour, “Mais, madame,
comment est que ça se fait?” He, worthy man, had but one idea of
the toilet in question, which he had gained from the Highland
regiments in the Crimea. I am happy to say, both for their own sakes
and their husbands and fathers, that the Englishwomen are by far
the most simply dressed. The men generally speaking are clad like
rational beings, but with many exceptions. I hear of a celebrity in
gray velvet knickerbockers and pink silk stockings, but have not seen
him. A man in a black velvet suit, and a red beard reaching his
waist, has just walked past, without apparently exciting wonder in
any breast but that of your contributor.
Dieppe must be a paradise to the rising generation. The children
share all the amusements of their elders, and have also special
entertainments of their own, amongst which one notes specially two
balls a week at the establishment. The whole building is brilliantly
lighted every evening, and on these nights the space under the
central dome is cleared of chairs, and makes a splendid ballroom.
Here the little folk assemble, and go through the whole performance
solemnly, just like their elders. The raised permanent seats are
occupied by mammas, nurses, governesses, and the public. The girls
sit round on the lowest seats, and the boys gather in groups talking
to them, or walking about in the centre. They are of all nations, in all
costumes—one boy in a red Garibaldian blouse and belt I noted as
the most dangerous flirt. There were common English jackets and
trousers, knickerbockers of many colours, and many little blue
French uniforms. There was no dancer older than fifteen, and some
certainly as young as seven. When the music began, the floor was at
once covered with couples, who danced quadrilles, waltzes, and a
pretty dance like the Schottische, to the tune of “When the green
leaves come again.” At the end of each dance the girls were handed
to their chairs with bows worthy of Beau Brummel. There were at
least 200 grown folk looking on, and a prettier sight I have seldom
seen, for the children danced beautifully for the most part. Should I
like my children to be amongst them? That is quite another affair. On
the whole, I incline to agree with the ladies with whom I went, that
it would, perhaps, do boys good, but must be utterly bad for the
girls. I certainly never saw before so self-possessed a set of young
gentlemen as those in question, and doubt if any one of them will
ever feel shy in after-life.
Last Sunday afternoon: again, we had a fete des vacances for the
children. The Gazette des Bains announced, “À deux heures,
ascensions grotesques, l’enlèvement du phoque; à deux heures et
demie, distribution de jouets et bonbons; à trois heures, course à
ânes, montés par des jockeys grosse-tête,”—a most piquant
programme. Not to mention the other attractions, what could the
enlèvement du phoque be? In good time I went into the
établissement grounds at the cost of a franc, and was at once
guided by the crowd to the brink of a small pond, where sure
enough a veritable live seal was swimming about, asking us all as
plainly as mild brown eyes could speak what all the rout meant, and
then diving smoothly under, to appear again on the other side of the
pond. Were the cruel Frenchmen actually going to send the gentle
beast up into the air? My speculations were cut short by the first
comic ascent and the shouts of the juveniles. A figure very like
Richard Doyle’s Saracens in the illustrations to Rebecca and Rowena,
with large head, bottle nose, and little straight arms and legs,
mounted suddenly into the air, and went away, wobbling and
bobbing, before the wind. Another and another followed, as fast as
they could be filled with gas. The wind blew towards the town, and
there was great excitement as to their destiny, for they rose only to
about the height of the houses. I own I was surprised to find myself
so deeply interested whether the absurd little Punchinellos would
clear the chimneys. One only failed, a fellow in a three-cornered hat
like a beadle’s, and, refusing to mount, was soon torn in pieces by
the boys. The last was a balloon of the figure of a seal, and I was
much relieved when we all trooped away to the distribution of
bonbons, leaving the real phoca still gliding about in his pond with
wondering eyes. The bonbons were distributed in the most polite
manner, the handfuls which were thrown amongst the crowd only
calling forth a “Pardon Monsieur,” “Pardon Mademoiselle,” as they
were picked up, instead of the hurly-burly and scramble we should
have had at home. The donkey races might better be called
processions, which went three times round the établissement. The
winner was ridden by a jockey whose grosse tête was that of a cock,
in compliment, I suppose, to the national bird; the lion jockey was
nowhere, but he beat the cook’s boy, who came in last. The figures
were well got up, and some of the heads really funny. At night we
had fireworks, and a grand pyrotechnic drama of the taking of the
old castle, which stands on the chalk cliff right over the
établissement and commanding the town. The garrison joined in the
fun, and assaulted the walls twice amidst discharges of rockets and
great guns. The third assault was successful, and the red-legged
soldiers swarmed on the walls in a blaze of light and planted the
tricolour. A brilliant scroll of “Vive l’Empéreur” came out on the dark
castle walls above their heads, and so the show ended. The castle,
by the way, is a most picturesque building. One of the towers has
been favourably noticed by Mr. Ruskin. It is also to be reverenced as
the stronghold of Henry IV. and the Protestants. It was here, just
before the battle of Arques, that he made the celebrated answer to a
faint-hearted ally, who spoke doubtfully as to the disparity of
numbers, “You forget to count God and the good cause, who are on
our side.” It will never be of any use in modern warfare, but makes a
good barrack and a most magnificent place for a pyrotechnic display
for the delectation of young folk, in which definition for these
purposes may be included the whole of the population of France.
As I am writing, a troop of acrobats pass along the green between
this hotel and the sea, followed by a crowd of boys. There is the
strong man in black velvet carrying the long balancing triangle, on
which he is about to support the light fellow in yellow who walks by
his side.
There is an athletic fellow in crimson breeches, carrying a table on
his head, and a clown with two chairs accompanying. There they
have pitched on the green, and are going to begin, and the English
boys are leaving their cricket, and the French boys their kites and
indiarubber handballs, and a goodly ring is forming, out of which, if
they are decent tumblers, I hope they may turn an honest franc or
two.
They are not only decent but capital tumblers, the best I have
seen for many a day, especially the man in crimson. He has balanced
three glasses full of water on his forehead, and then lain down on
his back, and passed himself, tumblers and all, through two small
hoops. He has placed one chair upon the table, and then has tilted
the second chair on two legs upon the seat of the first, and on this
fearfully precarious foundation has been balancing himself with his
legs straight up in the air while I could count thirty! The strong man
has just run up behind the man in yellow, who was standing with his
legs apart, and, stooping, has put his head between the yellow
man’s legs and thrown him a backward somersault! I must positively
go down and give them half a franc. It is a swindle to look on at
such good tumbling for nothing.
 P.S.—Imagine my delight, sir, when I got down on the green to
find they were the tumblers of my native land. They joined a French
circus for a tour some weeks back, but could get no money, and so
broke off and are working their way home. They can speak no
French, and find it very difficult to get leave to perform, as they have
to do in all French towns. The crowd of English boys seemed to be
doing their duty by them, so I hope they will speedily be able to
raise their passage-money and return to the land of double stout
and liberty.
 Normandy, 20th September 1863.

T
o an Englishman with little available spare cash and time, and
in want of a thorough change of scene and air, which category
I take to include a very handsome percentage of our fellow-
countrymen, I can recommend a run in Normandy without the
slightest hesitation. I am come to the age when one learns to be
what the boys call cocksure of nothing in this world, but am,
nevertheless, prepared to take my stand on the above
recommendation without fear or reservation. For in Normandy he
will get an exquisitely light and bracing air, a sky at least twice as far
off as our English one (which alone will raise his spirits to at least
twice their usual altitude), a pleasant, lively, and well-to-do people, a
picturesque country, delicious pears, and, to an Englishman, some of
the most interesting old towns in the world out of his own island. All
this he may well enjoy for ten days for a five-pound note, or
thereabouts, in addition to his return fare to Dieppe or Havre. So let
us throw up our insular vacation wide-awakes, and bless the men
who invented steam, and pears, and Norman architecture, “and
everything in the world beside,” as the good old song of “the
leathern bottèl” has it, and start for the fair land from which our last
conquerors came before the days get shorter than the nights. Alas!
how little of that blissful time now remains to us of the year of grace
1863.
It is some few years, I forget how many, since I was last in a
Norman town, and must confess that in some respects they have
changed for the better, externally at least, now that the Second
Empire has had time to make itself felt in them. All manner of police
arrangements, the sweeping, lighting, and paving, are marvellously
improved, and there is an air of prosperity about them which does
one good. Even in Rouen, the centre of their cotton district, there
are scarcely any outward signs of distress, although, so far as I
could see, not more than one in three of the mills is at work. I was
told that there are still nearly 30,000 operatives out of work in the
town and neighbourhood, who have no means of subsistence except
any odd job they can pick up to earn a few sous about the quays
and markets, but if it be so they kept out of sight during my
wanderings about the town. But there is one characteristic sign of
the empire to be noted in all these same Norman towns, for which
strangers will not feel thankful, though the inhabitants may. The
building and improving fever is on them all. In Rouen, amongst
other improvements, a broad new street is being made right through
some of the oldest parts of the town, from the quays straight up to
the boulevards, which it joins close by the railway-station. This
Grand Rue de l’Empereur will be a splendid street when finished, to
judge by the few houses which are already built at the lower end.
Meantime, the queer gables of the houses whose neighbours have
been destroyed, and a chapel or two, and an old tower, standing out
all by itself, which would make the architectural fortune of any other
city, and which find themselves with breathing room now, for the
first time, I should think, in the last five hundred years, look down
ruefully on the cleared space, in anticipation of the hour rapidly
approaching, when they will be again shut out from human ken by
four-storied stone palaces, and this time, undoubtedly, for good and
all. They can never hold up until another improving dynasty arrives.
At Havre the same process is going on. New houses are springing
up all along the new boulevards. Between the town and Frescati’s
great hotel and bathing establishment, which faces the sea, there
used to stand a curious old round tower of great size, which
commanded the mouth of the harbour, and some elaborate
fortifications of more modern date. All these have been levelled, old
and new together, and the ground is now clear for building, and will,
no doubt, be covered long before I shall see it again. Large seaports
are always interesting towns, and Havre, besides the usual
attractions of such places, has a sort of shop in greater perfection
than any other port known to me. In these you can buy or inspect
curiosities, alive and dead, from all parts of the world. Parrots of all
colours of the rainbow scream at the door, long cages full of love-
birds, and all manner of other delicate little feathered creatures one
has never seen elsewhere, hang on the walls, or stand about
amongst china monsters, and cases of amber, and inlaid stools from
Stamboul, and marmoset monkeys, and goodness knows what other
temptations to solvent persons with a taste for collections or pets. To
neither of these weaknesses can I plead guilty, so after a short
inspection I stroll to the harbour’s mouth, and do wonder to think
over the astounding audacity of our late countryman, Sir Sidney
Smith, who ran his ship close in here, and proceeded in his boats to
cut out a French frigate under the guns of the old fortifications. His
ship got aground, and was taken; he also. But, after all, it was less
of a forlorn hope than throwing himself with his handful of men into
Acre, and facing Bonaparte there, which last moderately lunatic act
made him a name in history. Audace! et encore d’audace! et
toujours d’audace! was the rule which brought our sailors
triumphantly through the great war. And there is another picture in
that drama which Havre harbour calls up in the English mind, to put
in the scale against Sir Sidney’s failure—I mean Citizen Muskein and
his gunboats skedaddling from Lieutenant Price in the Badger. Do
you remember, sir, Citizen Muskein’s—or rather Canning’s—inimitable
address to his gunboats in the Anti-Jacobin?—

Gunboats, unless you mean hereafter

To furnish food for British laughter,
Sweet gunboats, and your gallant crew,
Tempt not the rocks of St. Marcou,
Beware the Badger’s bloody pennant
And that d——d invalid Lieutenant!

Enough of war memories, and for the future the very last thing
one wishes to have to do with this simple, cheery, and, for all I can
see, honest people, is to fight them.
There are packets twice a day from Havre across the mouth of the
Seine, a seven miles’ run, to Honfleur, described in guide-books as a
dirty little town, utterly without interest. I can only say I have
seldom been in a place of its size, not the site of any great historic
event, which is better worth spending an afternoon in, and I should
strongly advise my typical Englishman to follow this route. In the
first place, the situation is beautiful. From the steep wooded heights
above the town, where are a chapel, much frequented by sailors,
and some villas, there are glorious views up the Seine, across to
Havre, and out over the sea. Then, in the town, there is the long
street, which runs down to the lighthouse, and which, I suppose, the
guide-book people never visit, as it is out of the way. It is certainly
as picturesque a street as can be found in Rouen, or any other
French town I have ever seen—except Troyes, by the way. The
houses are not large, but there is scarcely one of them which Prout
would not be proud to ask to sit to him.
Then there is the church in the centre of the town by the market-
place, with the most eccentric of little spires. It seems, at an early
period of the Middle Ages, to have taken it into its clock—or
whatever answers to a spire’s head—that it would seer more of the
world, and to have succeeded in getting about thirty yards away
from its nave. Here, probably finding locomotion a tougher business
than it reckoned on, it has fallen asleep, and, while it slept, several
small houses crept up against its base and fell asleep also. And there
it remains to this day, looking down over the houses in which people
live, and many apples and pears are being sold, and crying, like the
starling, “I can’t get out.” There is a splendid straight avenue,
stretching a mile and a half up the Caen road, and a good little
harbour full of English vessels, which ply the egg and fruit trade, and
over every third door in the sailors’ quarter you see “Cook-house”
written up in large letters, for the benefit of the British sailor.
The railway to Lisieux passes through a richly wooded, hilly
country, and then runs out into the great plain in which Caen lies.
The city of William the Conqueror is quite worthy of him, which is
saying a good deal. For, though one may not quite share Mr Carlyle’s
enthusiasm for “Wilhelmus Conquestor,” it must be confessed that he
is, at least, one of the three strongest men who have ruled in
England, and that in the long run he has done a stroke of good work
for our nation. The church of the Abbey des Hommes, which he
began in 1066, and of which Lanfranc was the first abbot, stands
just as he left it, except the tops of two towers at the west end,
which were finished two centuries later. It is a pure Norman church,
320 feet long, and 98 feet high in the nave and transepts, and the
simplest and grandest specimen of that noble style I have ever seen.
William’s grave is before the high altar, the spot marked by a dark
stone, and no king ever lay in more appropriate sepulchre. The
Huguenots rifled the grave and scattered his bones, but his strong
stern spirit seems to rest over the place. There is an old building
near the Abbey surmounted by a single solid pinnacle, under which
is a room which tradition says he occupied. It is now filled with the
wares of a joiner who lives below. Caen is increasing in a solid
manner in its outskirts, but seems less disturbed and altered by the
building mania than any of her sisters. There was an English
population of 4000 and upwards living here before 1848, but the
English Consul fairly frightened them away by assurances of his
inability to protect them (against what does not seem to have been
settled) in that wild time, and now there are not as many hundreds.
One of the survivors is the Commissionaire of the Hôtel d’Angleterre,
West by name, a really intelligent and serviceable man, well up to
his work. It is scarcely ever worth while to spend a franc on a
commissionaire, but West is an exception to the rule. His father was
in the lace trade, which is active in Caen, but his premises were
burnt down some years since, and an end put to his manufacture.
West is now trying to revive the family business, and one of his first
steps was to get over a new lace machine, and a man to work it,
from England. It has not proved a good speculation as yet, for no
one else can manage the machine, and the Englishman insists on
being drunk half his time.
 We left by one of the steamers which ply daily from Caen to
Havre. The run down the river is chiefly interesting from the quarries
on its banks. They are not the principal quarries, but are of very
considerable extent; and from the quantities of tip, heaped into
moderate-sized grass-covered hills by the river side, it is plain that
they must have been in work here for centuries. You see the stone
in many places lying like rich Cheddar cheese, and cut as regularly in
flakes as a grocer would cut his favourite cheeses. The stone is very
soft when it comes first from the quarries, but gains its great
hardness and sharpness after a short exposure. After passing the
quarries we got between salt marshes haunted by abundance of jack
snipe, and so we passed out to sea.
 Gleanings from Boulogne

T
here is one large portion of the French people which has
improved marvellously in appearance in the last few years,
and that is the army. The setting up of the French soldier of
the line used to be much neglected, but now you never see a man,
however small and slight, who does not carry himself and move as if
every muscle in his body had been thoroughly and scientifically
trained. And this is the actual fact. They have the finest system of
military gymnastics which has ever been seen. In every garrison
town there is a gymnasium, in which the men have to drill as
regularly as on the parade-ground. The one close to the gate of the
old town of Boulogne is an admirable specimen, and well worth a
visit. Our authorities are, I believe, slowly following in the steps of
the French, but little has as yet been done. There is no branch of
army reform which may more safely be pressed on. We have
undoubtedly the finer material. The English soldier is a bigger and
more muscular man than the French soldier, but is far behind him in
his physical education, and must remain so until we provide a proper
system of gymnastic training, which, by the bye, will benefit the
general health of the men, and develop their intelligence as well as
their muscles.
During our stay at Boulogne there was some very heavy weather.
A strong sou’-wester came on one night, and by two o’clock next
day, when I went down, was hurling the angry green waves against
the great beams of the southern pier in fearful fashion. The entrance
to the harbour, as most of your readers will remember, is quite
narrow, not one hundred yards across between the two pier heads.
The ebb-tide was sweeping down from the north, and, meeting the
gale right off the harbour’s mouth, made a battling and raging sea
which brought one’s heart into one’s mouth to look at. The weather
was quite bright, and though the wind was so strong that I held my
hat on with difficulty, the northern pier was crowded, as the whole
force of the sea was spent against the southern pier, over which it
was leaping every moment. We were in comparative shelter, and
could watch, Without being drenched with spray, the approach of
one of the fishing smacks of the port, which was coming home. I
shall not easily forget the sight. We stood there, jammed together,
rough sailors, fishwomen, Cockneys, weatherbound soldiers, well-
dressed ladies, a crowd of all ranks, the wind singing through us so
that we could scarcely make our nearest neighbours hear. Not that
we wanted to talk. The sight of the small black hull and ruddy brown
sail of the smack, now rising on the crest of a great wave, and the
next moment all but disappearing behind it, took away the desire,
almost the power, of speech. Two boats, manned with fishermen,
pulled to the harbour’s mouth, and lay rolling in the comparatively
still water just within the shelter of the southern pier head. It was
comforting to see them there, though if any catastrophe had
happened they could never have lived in that sea. But the gallant
little smack needed no help. She was magnificently steered, and
came dancing through the wildest part of the race without shipping
a single sea, seeming to catch each leaping wave just in the spot
where it was easiest to ride over. As she slid out of the seething
cauldron into the smooth water past the waiting boats the crowd
drew a long breath, and many of us hurried back to get a close view
of her as she ran into her place amongst the other fishing boats
alongside the quay. I envied the grizzly old hero at the helm, as he
left his place, threw off his dreadnought coat, and went to help the
two men and two boys who were taking in the sail and coiling away
the ropes. There was much shouting and congratulation from above;
but they made little answer, and no fuss. Their faces struck me very
much, especially the boys’, which were full of that quiet self-
contained look one sees in Hook’s pictures. There was no other boat
in the offing then, so I went home; but within a few hours heard
that a smack had capsized in the harbour’s mouth, with the loss of
one man. I only marvel how the rest could have been saved.
 On the 1st of October in every year there is a solemn festival of
the seafaring people of Boulogne, and the sea is blessed by their
pastors. I was anxious to wait for the ceremony, but was unable to
do so. There seems to be a strange mixture of trust in God and
superstition in all people who “occupy their business on the great
waters.” There is a little chapel looking down on Boulogne port full of
thank-offerings of the sailors’ wives, where the fishwomen go up to
plead with God, and pour out the agony of their souls in rough
weather. There are propitiatory gifts, too, by the side of the thank-
offerings, and the shadow of a tyrannous power in nature, to be
bought off with gifts, darkens the presence of the true Refuge from
the storm. There are traces, too, of a more direct idolatry in the
town. In the year 643 of our era the Madonna came to Boulogne in
an open boat, so runs the story, and left an image with the faithful,
which soon became the great religious lion of the neighbourhood,
drawing largely, and performing a series of miracles all through the
Middle Ages. When Henry VIII. took the town the English carried off
the image, but it was restored in good condition when peace came,
and as powerful as ever for wonder-working. The Huguenots got
hold of it half a century later, and were supposed to have destroyed
it; but an image, which at any rate did duty for it, was ultimately
fished up out of a well. Doubts as to identity, however, having
arisen, the matter was referred to the Sorbonne, and a jury of
doctors declared in favour of the genuineness of the article which
was forthcoming. And so it continued to practise with varying
success until the Revolution, when the Jacobins laid hands on it,
broke it up, and burnt it, thinking to make once for all an end of this
and other idol-worships. But a citizen not so enlightened as his
neighbours stayed by the fire, and succeeded at last in rescuing
what he declared to be an arm of the original image, which remains
an object of veneration still, and is said not to have lost all healing
power. But it is far inferior in this respect to some drops of the holy
blood, for the reception of which a countrywoman of ours has built a
little chapel in the suburbs.
 Boulogne has all the marks of rapidly increasing material
prosperity which may be seen now in every French town, one of the
many fruits of which is a wonderful improvement in the condition of
the streets and thoroughfares. The fine new buildings, the look of
the shops and of the people, all tell the same tale. In fact, one
comes away from France now with a feeling that, so far as surface
polish and civilisation are concerned, this is the country which is
going to the front. Whether it goes any deeper is a matter upon
which a traveller flitting about for a few weeks cannot venture an
opinion.
I came back in one of the daily packets to London Bridge, which,
besides carrying seventy passengers, was piled fore and aft with
cargo. There were 400 cases of wine on deck, besides other
packages, which sorely curtailed our walking privileges. But the
boats are good boats, and the voyage past Dover, through the
Downs, round the North Foreland, and up the Thames, is so full of
life and interest that it is well worth making a long day of it, if one is
a moderately good sailor. The advertisements call it eight and a half
hours, which means eleven; but it is not a moment too long.
 Blankenberghe

Y
esterday (14th August) we were warned by meagre fare at the
table d’hôte of our hotel that it was the vigil of some saint’s
day. Our gastronomic knowledge was enlarged by the
opportunity of partaking of boiled mussels. A small and delicate
species of this little fish—despised of Englishmen—is found in
extraordinary quantities on this coast. The sand is dotted with the
shells after every ebb. The wattles of the jetties are full of them.
After the first shock of having a salad bowl full of small black shells
presented to one, following immediately on a delicate potage à
l’oseille, the British citizen may pursue his education in this direction
fearlessly, with the certainty of becoming acquainted with a delicate
and appetising morsel; and he will return to his native country with
at least a toleration for “winks” and “pickled whelks,” when he sees
them vended at corner stalls in Clare Market or in the Old Kent
Road, for the benefit of the dangerous classes of his fellow-citizens
who take their meals in the street. In these Flemish parts they are
eaten with bread and butter, and even as whitebait, and by all
classes.
After the meal I consulted the calendar in my pocket-book as to
the approaching festival, not wishing to thrust my heretical
ignorance unnecessarily on the notice of the simple folk who inhabit
the Lion d’Or. That obstinately Protestant document, however,
informed me simply that the Rev. E. Irving was born on this day in
1792, probably not the saint I was in quest of. A Churchman’s
Almanac, with which the only English lady in the place was provided,
was altogether silent as to the day. In the end, therefore, I was
obliged to fall back upon the bright-eyed little demoiselle de la
maison, who informed me that it was the vigil of the Assumption of
the Virgin, and that the fête was one greatly honoured by the
community of Blankenberghe.
 Thus prepared, I was not surprised at being roused at five in the
morning by the clumping of sabots and clinking of hammers in the
street below—my room is a corner one, looking from two windows
on the Rue d’Eglise, the principal street of the place, and from the
other two on the Rue des Pecheurs, or “Visschurs’ Straet,” which
runs across the northern end of the Rue d’Eglise. A flight of broad
steps here runs up on to the Digue, or broad terrace fronting the
sea, and at the foot of these steps they were erecting a temporary
altar, and over it a large picture of fishermen hauling in nets full of
monsters of the deep. They had brought it from the parish church,
and, as such pictures go, it was by no means a bad one. Presently
tricoloured flags began to appear from the windows of most of the
houses in both streets, and here and there garlands of bright-
coloured paper were hung across from one side to the other. As the
morning advanced the bells from the church and convent called the
simple folk to mass at short intervals, six, half-past seven, nine, and
grand mass at ten. The call seemed to be answered by more people
than we had fancied the town could have held. At eleven there was
to be a procession, and now miniature altars with lighted candles
appeared in many of the ground-floor windows, both of shops and
private houses; and the streets were strewed with rushes and
diamond-shaped pieces of coloured paper. Punctual to its time the
head of the procession came round the corner of “Visschurs’ Straet,”
half a dozen small boys ringing bells leading the way. Then came the
beadledom of Blankenberghe, in the shape of several imposing
persons in municipal uniform, then three little girls dressed in white,
with bouquets, more boys, including a diligent but not very skilful
drummer, six or seven other maidens in white, somewhat older than
their predecessors, of whom the centre one carried some ornament
of tinsel and flowers. Then came the heavy silk canopy, supported
by four light poles carried by acolytes, and surrounded by choristers,
of whom the leader bore a large silver censer, and under the canopy
marched a shaven monk in cream-coloured brocade satin, carrying
the pyx, and a less gorgeously attired brother with an open missal.
Around the whole of the procession, to protect it from the
accompanying crowd, were a belt of bronzed fishermen in their best
clothes, some carrying staves, some hymn-books, and almost all
joining in the chant which was rolled out by the priest, in a powerful
bass with a kind of metallic ring in it, as they neared the altar at the
foot of the steps. Here the whole procession paused, and the greater
part knelt, while the priest put incense in the censer, and made his
obeisances and prayed in an unknown tongue, and the censer boy
swung his sweet-smelling smoke about, and the fishermen and their
wives and children prayed too, in their own tongue, I suppose, and
their own way, probably for fair weather and plenty of fish, and let
us hope for brave and gentle hearts to meet whatever rough
weather and short commons may be in store for them by land or
water, Then the procession rose, and passed down the Rue d’Eglise,
pausing at the corner of the little market-place opposite a rude
figure of the Madonna in a niche over some pious doorway, [Greek
phrase] and so out of sight. And the bourgeois blew out the candles
and took away the chairs on which, while the halt lasted, they had
been kneeling from their shop windows, putting back the bathing
dresses, and the shell boxes, and other sea-side merchandise, while
the whole non-shopkeeping population, and the neighbours from
Bruges, and the strangers who fill the hotels and lodging-houses
turned out upon the splendid sands and on the Digue to enjoy their
fête-day. In the afternoon the corps de musique of the communal
schools of Bruges gave a gratuitous concert to us all by the
permission of the communal administration of that town, as we
bathed, or promenaded, or sipped coffee or liqueurs in the broad
verandahs of the cafés which line the Digue. Gaily dressed middle-
class women (of upper classes, as we understand them, I see none),
in many-coloured garments and immense structures of false back
hair, such as these eyes have never before seen; a sprinkling of
Belgian officers in uniform, Russians, Frenchmen, Germans a few,
and two Anglo-Saxons, Englishmen I cannot say, for one is an
American citizen and the other your contributor, who compose the
only English-speaking males, so far as I can judge; groups of
Flemish women of the people in long black cloth cloaks, with large
hoods lined with black satin, more expensive probably, but not
nearly so picturesque as the old red cloak which thirty years ago was
the almost universal Sunday dress of women in Wiltshire, Berkshire,
and other Western counties; little old-fashioned girls in nice mob
caps, and the fishermen in excellent blue broad-cloth jackets and
trousers, and well-blacked shoes or boots, instead of the huge
sabots of their daily life; in short, every soul, I suppose, in
Blankenberghe, from the Bourgmestre who sits on his throne, to the
donkey-boy who drives along his Neddy under a freight of children,
at half a franc an hour, whenever he can entice the small fry from
the superior attraction of engineering with the splendid sand, spends
his or her three or four hours on the Digue, enjoying whatever of the
music, gossip, coffee, beer, or other pastimes they are inclined to or
can afford; and in that whole crowd of pleasant holiday-making folk
there is not one single trace of poverty, not a starved face, not a
naked foot, not a ragged garment. It is the same on the week-days.
The people, notably the fishermen and baigneurs, dress roughly, but
they have all comfortable thick worsted stockings in their sabots,
and their jerseys and overalls are ample and satisfactory. Why is it
that in nine places out of ten on the Continent this is so, and that in
England you shall never be able to find a watering-place which is not
deformed more or less by poverty and thriftlessness? Right across
the sea, there, on the Norfolk coast, lie Cromer and Sherringham.
More daring sailors never manned lifeboat, more patient fishermen
never dragged net, than the seafaring folk of those charming
villages. They are courteous, simple, outspoken folk, too, singularly
attractive in their looks and ways. But, alas! for the rags, and the
grinding poverty, declaring itself in a dozen ways, in the cottages, in
the children’s looks, in the women’s premature old age. When will
England wake up, and get rid of the curse of her wealth and the
curse of her poverty? When will an Englishman be able again to look
on at a fête-day in Belgium, or Switzerland, or Germany, or France,
without a troubled conscience and a pain in his heart, as he thinks of
the contrast at home, and the bitter satire in the old, worn-out name
of “Merry England?” It is high time that we all were heartsick over it,
for the canker grows on us. Those who know London best will tell
you so; those who know the great provincial towns and country
villages will tell you so, except perhaps that the latter are now
getting depopulated, and so contain less altogether of joy or sorrow.
However, sir, there are other than these holiday times in which to
dwell on this dark subject. I ought to apologise for having fallen into
it unawares, when I sat down merely to put on paper, if I could in a
few lines, and impart to your readers the exceeding freshness of the
feeling which the feast-day at this little Belgian watering-place leaves
on one. But who knows when he sits down, at any rate in the
holidays, what he is going to write? However good your intentions,
at times you can’t “get the hang of it,” can’t say the thing you meant
to say.
You may wonder, too, at this sudden plunge into the fête of the
Assumption at Blankenberghe, when I have never warned you even
that I had flitted from my round on the great crank which grinds for
us all so ruthlessly in the parts about the Strand and the Inns of
Court. Well, sir, I plead in my defence the test that a very able friend
of mine applies to novels. He opens the second volume and reads a
chapter; if that tempts him, on he goes to the end of the book; if it
is very good indeed, he then goes back, and fairly begins at the
beginning. So I hope your readers will be inclined to peruse in future
weeks some further gossip respecting this place, which should
perhaps have preceded the fête-day. If they should get to take the
least interest in Blankenberghians and their works and ways, it is
more than these latter can be said to do about them, for in the two
or three cheap sheets which I find on the table here, and which
constitute the press of this corner of Belgium, there is seldom more
than a couple of lines devoted to the whole British Empire. The fact
that there is not another Englishman in the place, and that the
American above mentioned, the only other representative of our
English-speaking stock here, went once to see the Derby, and got so
bored by two o’clock that he left the Downs and walked back to
Epsom station, enduring the whole chaff of the road, and finding the
doors locked and the clerks and porters all gone up to the race,
ought to be enough to make them curious—curious enough at any
rate for long-vacation purposes. There are plenty of odds and ends
of life a little out of our ordinary track lying about here to make a
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