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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
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
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.)
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.
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).
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
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whom we test its practical value is the preacher. Emerson remarked,
“What you are thunders so loud I cannot hear what you say.”
No great writer of modern times has written more persuasively of
the Christian way of life than Tolstoi; there is no doubt that his stories
and tracts have had an immense influence on millions of readers and
have inspired them toward unselfishness, kindness and humility. But
of all great Russian writers, Tolstoi himself was the most difficult to
get along with; he could not bear to hear any other writer praised and
was lacking in the grace of appreciation. His rival, Turgenev, who
had no religious belief of any kind, excelled Tolstoi in the virtues of
modesty, unselfishness and consideration for others.
One of the many reasons why the art of bringing up children is
the most difficult of all arts is that it is essential for parents to set a
daily example. All the moral precepts in the world will not seriously
impress children if their parents do not in their daily life come
somewhere near the ideals they hold up. The child will after a
fashion love his parents anyhow, but as he grows older and begins
to compare what he has been taught with what he sees, the child is
transformed into a judge. This partly explains that fear of their own
children which so many parents secretly feel.
If the parents make their small children go to church and stay
home themselves, the children quite naturally regard church-going
as one of the numerous penalties imposed on youth and look
forward to maturity as an escape from this and many other
unpleasant compulsions. If parents impress on their children the
necessity of telling the truth, they must not themselves tell lies; they
are being watched by the sharpest eyes in the world.
Although in a certain sense we are all hypocrites—for no one
can live up to his ideals—we hate any flagrant case of hypocrisy. I
suppose one reason we have a sneaking admiration for pirates is
that pirates are not hypocrites. There is no doubt that professional
pirates are more generally admired than professional politicians. I do
not say that politicians are hypocrites; I say that pirates are not.
It is the personalities of great leaders, much more than their
sayings, that have had a beneficial influence. The sayings of Jesus
—every word that has come down to us—can be read through in
three hours. But from His life and character flows a vital force,
tremendously effective after nineteen centuries. Very few people
read the literary compositions of Sir Philip Sidney, but millions have
been influenced by his life and character. The pure, unselfish life of
George Herbert is more efficacious than his poems; and consider
Saint Francis!
The Christian Church has had in every century of its existence
able, honest, determined foes, who have done their best to destroy
it; it is probable that they have done it no injury. Nor have the frank
sensualists and materialists hurt it at all. It has been injured only by
its professed friends.
If a physician opens an office, his most dangerous foes are not
his competitors, that is to say, other doctors; his most dangerous
foes are those of his patients who say, “Well, I took his medicine, and
it did me no good.” The best advertising is done by one’s sincere
friends and admirers; the good word about the new doctor, or the
new novel, or the new play, is passed along.
The Christian religion professes to make those who accept it
better and happier; every one who professes it and exhibits none of
its graces is a powerful argument against its validity. A man’s foes
are those of his own household.
Sometimes I think religion should first of all show itself in good
manners; that is, in true politeness, consideration for others,
kindness and deference without servility. Such persons are those we
love to meet and be with; they are good advertisements of their
religion; they will not have to talk about it because its effects are so
plainly and attractively seen.
XXV
LONDON AS A SUMMER RESORT
I had an interesting conversation with Bernard Shaw last week.

The next day he and Mrs. Shaw were leaving to spend the summer
on the Riviera, which from time immemorial has been regarded as a
winter resort. He gave, as is his custom, an original and diverting
explanation of the fact that many now prefer to visit winter resorts in
the summer. It is a matter of clothes. The Victorians were forced to
go to cool places, or at any rate to avoid warm places; because they
were compelled to wear stuffy clothes, the men being encased in
frock coats, thick waistcoats, collars and swaddling neckcloths. But
today, when one leaves off almost everything, the finest place in the
world, according to G. B. S., is a climate where one can live outdoors
in comfort, day and night.
It is certainly true that many European resorts, where the hotels
used to be open only during a short winter season, now attract
visitors the year round. The converse is also true. I can well
remember when the great hotels of Switzerland—the playground of
Europe—were open only during the summer; and were crowded only
during the month of August. But now they never close and are as
much sought after in December and January as in the good old
summertime. The same is true of Lake Placid in America and of
many other places. People in Victorian times were forced to dress
according to the prevailing style, which bore no reference to climate
or common sense; remember how the women used to look, playing
golf and tennis!
Furthermore the old idea that everyone who could afford it must
leave the city during the “heated term” has become obsolete, even in
America. President Harper of the University of Chicago established a
Summer Quarter, and professors who wished to do so could take
their three months’ vacation in the winter, a privilege that many
continue to enjoy. The Country clubs and golf have had much to do
with the contentment of business men who remain in cities during
the summer. As a matter of fact, the city is not at all a bad place, I
mean, of course, for those who can afford to make themselves
comfortable.
The city of Munich has for many years been a Mecca for
summer pilgrims. The season of music, arranged for foreign visitors,
reaches its climax in August. Now I wish to urge the millions of
Americans who at one time or another cross the ocean to consider
the merits of London as a summer resort.
For over a hundred years July has been a part of the London
“season”; Parliament is in session, operas and theatres are open,
and parties flourish amain. The twelfth of August, the opening of the
grouse shooting season, is the formal beginning of the vacation;
Parliament always adjourns for it, and London society flies north. But
to an American London is day by day interesting, and there should
be no closing of any season for him.
London has no prolonged hot weather, like St. Louis. It has been
said that the English climate consists of eight months of winter, and
four months of bad weather. This is an exaggeration. Every now and
then there is a year when summer is omitted; but even in such an
unfortunate time, one is better off in London than in the country. In
fact, to an American London, while not the most beautiful city in the
world, is assuredly the most interesting. It is inexhaustible. Every foot
of it, to one well read in English literature, is hallowed ground; I think
I could walk along Fleet street a thousand days in succession, and
always receive a thrill.
I wish that every American journalist, every American book
reviewer, every American drama critic, would spend a month in
London and diligently read the morning newspapers, such as The
Times, The Telegraph, The Morning Post. Every page seems to be
written for intelligent readers. These London journalists review
tennis, golf and cricket matches with more dignity than the average
New Yorker reviews plays and books. One reason that militates
steadily against intellectual progress in America is the fact that
apparently we have no language suitable as a medium for the
exchange of ideas. Our book reviews and our drama criticisms are
too often written in a cheap kind of slang that is intended to be smart.
If anyone imagines that the journalism of London loses in intensity by
being written in suitable English, let him turn to a file of The London
Times and read the story of Tilden playing tennis at Wimbledon.
A remarkable thing about literary society in London is that age
has nothing to do with it. One meets in social gatherings men and
women in the twenties and in the eighties—disparity in years seems
to be forgotten.
One should remember that, owing to the small size of England,
one can use London as a base of operations and take excursions
into the country on the swift English trains, returning to London every
evening; many happy, baggageless days have I spent in this
manner.
When G. K. Chesterton was in America, I asked him what
difference between the two countries impressed him most. Instantly
he replied, “Your wooden houses.” I had never thought of them as
curiosities, but one does not see them in England. The thing that to
me is most noticeable on the London streets is the absence of straw
hats. There are many more bare male heads than there are straw
hats. It is almost impossible to attract attention in London, but a
straw hat will come nearest to doing the trick. Some men are
exquisitely and others strangely clad, and nobody cares. I saw a
man riding a bicycle. He had on tan shoes, homespun trousers, a
frock coat, and a tall silk hat.
XXVI
WHAT THE MAN WILL WEAR
Men, women, and children are all interested in clothes; there

have been many scholarly works, displaying vast erudition, on the
history of costume; and two literary masterpieces, dealing with the
philosophy of clothes, belong permanently to literature—A Tale of a
Tub, by Jonathan Swift, and Sartor Resartus, by Thomas Carlyle.
So much attention has recently been paid in the newspapers and
by the public to the clothes of women, that we are forgetting what
revolutionary changes have taken place in the garments of men.
Women’s clothes have decreased in number, weight, and size.
Men’s clothes have gone through a process of softening. Hard hats,
hard collars, hard shirts, hard shoes, hard suits, have given way to
soft; and, for the first time in centuries, the carcasses of males are
comfortably clad.
One hundred years ago the average gentleman, not satisfied
with covering his body with an accumulation of intolerably thick
clothes, wound an enormous stock around his neck. How stifling
they look in those old family portraits! Robert Louis Stevenson
applied an unexpected but accurate adjective to those collections of
oil paintings of deceased ancestors, with which their descendants
adorned walls of their dining rooms. Stevenson called them “these
constipated portraits.”
This is the way my father dressed on practically every morning of
his life; that is, after he left the farm, and entered upon the practice of
his profession. He wore long, heavy flannel underwear, reaching to
his ankles and his wrists. He put on a “hard-boiled,” white, full-
bosomed shirt, stiff as sheet-iron. At the neck he fastened a stiff,
upright, white linen choker collar; at the ends of the sleeves he
buttoned on thick, three-ply linen cuffs. He imprisoned his feet,
ankles, and shins in black, stiff, leather boots, reaching to the knees,
but concealed above the ankles by his trousers. He wore a long-
tailed coat, a waistcoat, and trousers made out of thick, dark-blue or
black broadcloth. The trousers were strapped over his shoulders by
suspenders. For the top of his head there was a tall, heavy, beaver
hat.
Thus, clad in impenetrable armour from head to foot, he set out
for the day’s work.
Fifty years ago was the age of dressing-gown and slippers. Why
is it we never hear slippers mentioned nowadays? I have not owned
a pair of slippers (except bedroom slippers) for more than thirty
years. Yet in Victorian novels we are always reading of how, when
the breadwinner returns to his home in the evening, he finds his
slippers ready for him, warmed on the hearth. My father always took
off his great boots—worn in summer as well as in winter—and put on
his slippers when he came home, having called it a day.
Poets, novelists, and men whose occupation kept them at home,
sat down to their desk in dressing-gown and slippers. The moment a
man sat down in his own house to anything, with no immediate
thought of going out, dressing-gown and slippers were the regulation
costume. They were like knights-at-arms, taking off their suits of mail
when they entered the interior of the castle.
Eventually the knee-boots gave way to high shoes—called boots
in England—which were laced up to the top. In time these were
succeeded by low shoes, which are now worn by millions of
Americans the year round.
The swaddling, stifling, heavy underclothes were scrapped, and
their place taken by sleeveless, shinless undergarments, light in
weight, and more or less open in texture. Best of all, the intolerable
stiff shirt, the bottom edge of which cut into the abdomen, and bellied
out above like a sail in a fair wind, was reserved only for formal
evening wear; shirts were made and worn that had no trace of starch
in front, back, collar or cuff. I have not worn a stiff shirt (except for
evening) in twenty years.
Suspenders (braces) became obsolete; and the pleasant belt
came in, the belt that may be loosened or tightened at will, and
which in any case leaves the shoulders free. In hot weather the
waistcoat was discarded; and the man in his thin, loose clothes
moved about almost as easily as Adam in Paradise.
Various are the names for the round stiff hat, derby, dicer, pot
hat, bowler, billy-cock. Under any name it is just as bad. Some fifteen
or twenty years ago the derby went temporarily out of fashion. Up to
that time, if you looked into a cloak-room by a hotel dining-room, you
saw about two hundred men’s hats looking exactly alike. Now you
see a vast assortment of soft headgear, grey, brown, green, all of
pleasing shape. The thousands of men at a football game now show
variety aloft, instead of the intolerable black monotony of former
years. I have not owned a “derby” since the war. Apart from my own
hatred of the object, I always crushed it getting in or out of an
automobile. And one indentation ruins a derby forever: every wound
is mortal.
I am quite aware that the derby is returning. Everyone knows the
nation-wide fame acquired by a certain brown derby. But no stiff hat,
black or brown, will ever adorn my brows again during the hours of
daylight.
The English, owing to their horrible climate and also partly to an
invincible conservatism, still wear heavy clothes, thicksoled high
shoes, braces, waistcoats, etc., even in hot weather. The only reform
they have made is discarding the frock coat for daily wear, which up
to a very few years ago was universal. A common sight in London
was to see clerks going to the “city” on bicycles, arrayed in “Prince
Albert” coats.
The clothes of an American tourist still look funny to an
Englishman; how funny I never realised until I attended a play in
London where an American was the object of good-natured
caricature. He came on the stage with low shoes and silk shoe-
laces, bright, thin socks, trousers held by a belt, no waistcoat, and
jacket unbuttoned. The audience burst into roars of laughter and I
laughed too, because he did look queer by contrast with the other
actors. Then I suddenly realised that I was dressed precisely like the
man they were laughing at!
One more reform must be made in men’s dress; and I believe it
will come. In very hot weather, men must be allowed to discard the
jacket. Even a thin jacket, with its collar and shouldercloth, is
intolerable. A clean, attractive shirt, with soft collar and necktie, and
belt around the trousers, looks so sensible in hot weather that it
ought to become the rule rather than the exception.
XXVII
DREAMS
I look upon horrible dreams as one of the assets of humanity,

one of the good things of life; because one feels so elated after
waking. I am convinced that most men and women do not sufficiently
appreciate the advantages they possess. They either exaggerate
their sufferings and drawbacks or, instead of enjoying what they
have, they spend their time in longing for what is beyond their reach.
Just as it takes an illness to make one appreciate the
satisfactions of health, so one needs a calamity to make one realise
how good daily existence really is. It is often said that experience is
the best teacher. This is by no means always or even often true.
Experience charges too much for her lessons.
There is no good in learning how one might have shown sagacity
in business after one is bankrupt; there is no good in discovering
how one ought to have avoided a certain article of diet after one is
fatally poisoned; there is no good in receiving the proof of the danger
in carelessly driving a motor car after one lies dead in the ditch.
Now the best way to discover how cheerful daily life may be is to
be visited by a frightful dream. The horrible wild beast has seized us,
because when we tried to flee, our legs were lead. Just as it is about
to sink its terrible tusks in our shrinking frame, we wake up, and hear
the good old trolley car go by. Hurrah! it was only a dream; and we
are alive on the blessed earth. And we have learned how sweet plain
ordinary life is without the lesson costing us anything but a transitory
sweat.
I think, too, that many who either profess to hate life or at all
events refuse to admit anything good about it, might appreciate it
more if they could be temporarily transferred, not to hell, but to their
own imagined heaven. Wagner in the famous music-drama,
Tannhäuser, has given an admirable illustration. This knight, like all
his fellow-creatures, felt the call of the senses; he was transported
from this imperfect earth to the pagan Heaven, where he lived in the
constant society of Venus. But after a time this palled upon him and
eventually became intolerable. He tore himself away, and suddenly
found himself back on the earth. He was in a green pasture in the
springtime, and a shepherd boy was singing—what happiness!
The accomplished German dramatist Ludwig Fulda wrote a play,
Schlaraffenland. There was a poor boy, ragged, cold and chronically
hungry. He dreamed he was in a magic land. Remarkable birds flew
so slowly by him that he found he could reach out his hand and
grasp them. He did this, and lo, he had in his hand a broiled chicken!
He ate several with avidity, but could not eat forever. Glancing at his
ragged garments, a wardrobe door flew wide, and he had his choice
among many elegant suits. Thus every desire was instantly and
abundantly gratified. After some time, this palled upon him, and then
became so unendurable that he gave a yell of horror; he woke up.
He was cold, ragged, and hungry; but his heart was singing. He was
back on the good old earth.
Thus, whether we dream of hell or of heaven, it is usually with a
sigh or even a shout of satisfaction that we find ourselves back on
this imperfect globe.
Many persons tell me that they never dream; their sleep is blank.
It is with me quite otherwise; I almost always dream; many of my
dreams are extraordinarily vivid and some are unforgettable.
When I was a child I dreamed three nights in succession of the
Devil. The first night the Devil chased me upstairs. I ran as fast as I
could, but sank down when only half way up. Then the Devil took
from his pocket a shoemaker’s awl and bored it deftly into my right
knee. The second night the Devil was in my front yard. Suddenly he
changed into the form of a dog; and when another dog rushed
barking at him the satanic hound swallowed him as easily as one
takes a pill. The third night I also dreamed of the Devil, but I have
forgotten the details.
One of the worst dreams I had in childhood was when I was
being attacked by wild beasts, and suddenly my mother appeared on
the scene. I shrieked to her for help, and she looked at me with calm
indifference. That was the worst dream I ever had, and you may be
sure it went by contraries.
I suppose the only way we can distinguish dreams from what is
called actual life is that in dreams the law of causation is suspended.
There is no order in events, and no principle of sufficient reason to
account for them. Things change in an impossible manner. Apart
from this, dreams are as real as life while they last.
I often have prolonged dreams that are not only fully as real as
waking experiences, but are orderly and sensible, and sometimes
delightful. Many years ago I dreamed that I was walking the streets
of a Russian city with Count Tolstoi. It was one of the most agreeable
and most inspiring days of my life, and I have always regretted it
never happened. We walked together for hours and discussed
modern literature. He said a great many wise and brilliant things, all
of which I have, alas, forgotten. The only feature of that dream unlike
reality was that Tolstoi had shaved off his beard.
Wilkie Collins, in Armadale, suggested that every dream we
have is a repetition of an experience that has actually happened to
us during the preceding twenty-four hours. I read that novel in my
boyhood and was impressed by that explanation of dreams, and for
several months I wrote down my dreams and found that every one
was suggested by something that had happened to me during the
preceding day.
The only thing I am certain of in dreams is that they do not in any
way forecast the future. When I was a child I dreamed I saw heaven
and Jesus sitting on a cloud. He called to me, “Willie Phelps, come
here.” The next day I told my father and mother about it, and to my
surprise they were exceedingly alarmed.
XXVIII
EATING BREAKFAST
In the daily life of the average person the longest interval between
eating is that between the evening meal and breakfast; the very name
for the morning repast accurately describes its nature. It should
therefore, be taken seriously, which means that there should not only
be enough to eat, but that plenty of time should be allowed to eat it.
I am aware that there are many men of excellent character who eat
almost nothing for breakfast, and that there are some saints who eat
no breakfast at all. In character and personal habits, I have never met
a man more saintly than Henry Ford. I refer both to the asceticism of
his physical life and to the purity of the motives that inspire his
conduct. He eats no breakfast at all, not a morsel of food. He rises
very early, goes outdoors, runs a mile or two and then works with
absolute concentration till one o’clock, when he has the first meal of
the day. I asked him if he never felt any desire for food during so long a
morning; he replied that it was necessary for him in his vast
undertakings to have a mind entirely fresh and clear, and that he found
he could do better work on an empty stomach and with a brain
unclouded by food.
I suppose every man must be a law unto himself. It does not seem
to me that I could live happily without breakfast, yet I am sure that it is
better to omit the meal altogether than to eat it in the hurry and fever in
which many Americans devour it. Far too many prefer to lie in bed half
an hour longer than to use that precious half hour in the consumption
of food.
* * * * *
In the days when they had required morning chapel at Yale a great
many students came to chapel either without any breakfast or with
unassorted junks of it in their stomachs engaged in civil war. One early
morning I was walking up Elm Street in New Haven; the streets ware
filled with undergraduates sprinting to chapel. The lady with me said:
“Do look at those poor boys running to chapel with their tongues
hanging out!” I set her right at once. “Those are not tongues, those are
griddle cakes!”
Those young men were accurate calculators. Three minutes for
breakfast, one minute to reach chapel. They hurried the last griddle
cake into their faces as they left the dining hall, and it gradually
disappeared as they ran.
I love to see the whole family assemble at breakfast and eat a
good meal leisurely. In order to accomplish this, every one must get up
early enough to allow for complete preparation in the way of bathing,
shaving, etc., and then leave enough time to consume food in peace of
mind. Of how many families is this true? Of course, there are many
persons who like to eat breakfast in bed, and perhaps, there are some
who can do this neatly, even artistically. I never eat breakfast in bed
unless I am too sick to get up, for I hate to have crumbs all over my
night clothes or inside the bed. Furthermore, in spite of considerable
practice during various illnesses, I have never mastered the fine art of
swallowing food while in a horizontal position. To take coffee in this
manner is an achievement. And what is breakfast without coffee?
Although coffee is not an American product, I have never had a
satisfactory cup of coffee outside of the United States of America.
Americans alone seem to understand the secret of good coffee. The
English meet this problem illegitimately, by substituting tea. Now tea is
all very well in the late afternoon, but in the morning it is without
inspiration. And every man ought to start the day in an inspired
manner.
G. K. Chesterton says that Bernard Shaw is like coffee; he
stimulates but does not inspire. I should amend that, by saying Shaw is
like coffee because he stimulates but does not nourish. For I firmly
believe that both Shaw and coffee are alike in this: they do both
stimulate and inspire, but they do not nourish. I used to wonder what
Chesterton could possibly mean by saying that coffee did not inspire,
when suddenly the true explanation occurred to me. He was thinking of
English coffee.
The newspaper should not be read during the sacred rite of
breakfast. There is no doubt that many divorces have been caused by
the man’s opening and reading the newspaper at breakfast, thereby
totally eclipsing his wife. It is simply a case of bad manners, and bad
manners at food have in thousands of instances extinguished the fires
of love. Nor, although it is a common custom, do I believe that letters
should be opened and read at the breakfast table. One letter may
contain enough worry, disappointment and anger to upset a reader for
hours. And to eat food while one is angry, or worried, or excited is
almost as bad as eating poison. I never read letters at breakfast and I
never read letters in the evening.
For the same reason breakfast should be eaten in a calm and
peaceful state of mind, illuminated by happy family conversation. Many
men every day eat breakfast in feverish haste and then run to catch a
trolley car or a train. That horrible breakfast soon begins to assert
itself, and the man is in an irritable condition all the morning. It simply
does not pay to eat in a hurry. Breakfast should not resemble a
delirium.
And at the breakfast table all the members of the party should eat
or leave the room. It is a sad experience to be in a hotel or in a dining
car and have some acquaintance come up briskly and say: “I have
already had my breakfast, but I will sit and talk with you while you eat
yours.” That means he intends to watch you eat, and, just as your
mouth is full of food, he will ask you a question. I have observed many
patient men suffering tortures in this manner. I have even observed an
enormous mass of unchewed food distend their throats as they hastily
bolt it in the endeavor to reply to interrogations. A snake may swallow
a toad, but the snake’s constitution differs from a man’s.
If I could have only one meal a day, it would be breakfast. After a
good American breakfast—orange juice, cereal, coffee, toast, bacon
and eggs—I am ready for everything and anything. If the day begins in
the right manner its progress will be satisfactory. And the best of all
rules of diet is to eat what you like and take the time to do it.
XXIX
THE MOTHER TONGUE
Judges xii:6—“Then said they unto him, Say now Shibboleth:

and he said Sibboleth: for he could not frame to pronounce it right.
Then they took him, and slew him at the passages of Jordan: and
there fell at that time of the Ephraimites forty and two thousand.”
If there were forty-two thousand of the sons of Ephraim who
could not speak correctly and distinctly, we may be sure that the
sons and daughters of America are not impeccable. Indeed, we have
daily evidence not only on the street and in railway coaches, but in
schools, churches, colleges and theatres, of linguistic matricide—
mortal attacks on the mother tongue, committed with impunity in the
absence of the axe. In Old Testament times they had, as we see by
the text of this sermon, drastic methods for establishing correct
standards of pronunciation; those who did not speak accurately were
eliminated.
Besides the suffering inflicted on sensitive and sympathetic ears,
there is a feeling of shame in the heart of this present evangelist that
the American public school, which ought to be a temple where the
English language is treated with reverence, should actually be a
scene of cynical—since everything careless is cynical—desecration.
I am not condemning colloquial slang, which in its metaphorical
picturesqueness is often the very life of speech, but rather the
shoddy mutilation of words in good and regular standing.
More important than the study of foreign tongues is the
unaffectedly correct pronunciation of that language which is now
heard in the uttermost parts of the earth. Furthermore, the very
difficulties of English pronunciation make the successful surmounting
of them a glorious achievement, one that should appeal to the Spirit
of Youth, which instinctively loves a desperate undertaking.
German is practically a phonetic language; leaving out the
matter of accent, it is easier for an American, with proper instruction,
to speak German words correctly than it is for him to conquer the
wild and lawless army of English syllables. Let us then not minimise
the strength of the foe; let this rather become an inspiration.
Let me say two things to all school and college teachers: No
matter what subject you teach, Greek, chemistry or physics,
whenever you hear one of your pupils mispronounce an English
word correct him so that he and the other members of the class will
learn something valuable there and then. And when you do this, tell
the class that if any member of it hears you mispronounce a word,
you will be grateful for immediate and public correction.
Second, do not allow any pupil to speak better English than that
spoken by you. Our schools and colleges contain a few pupils who
speak the language so well that they beat the teacher; the teacher
should not permit such a thing to continue. Although I was brought
up in a cultivated home, I learned in my boyhood a considerable
number of bad pronunciations; I changed these for better ones
because I was determined that no one of my students should speak
more correctly than I.
Bernard Shaw told me he was on a special committee appointed
to standardise English pronunciation in Great Britain; this committee,
consisting of a very few, tell all the radio broadcasters exactly how to
pronounce a long list of words, in the hope that by this means the
millions “listening in” will learn how to speak their own language.
There is no reason why Americans should imitate the British in
the pronunciation of certain words which the cultivated citizens of
both countries pronounce quite differently—I refer to words like
schedule, clerk, capitalist, trait, fracas, lieutenant and the last letter in
the alphabet which Shakespeare calls by a bad name.
It is sheer affectation to imitate the British in such special
matters, as it is an affectation to imitate what is called the Oxford
accent, where the word smoke is pronounced as if it were spelled
smilk—see Julian Street’s delightful book In Need of Change.
Yesterday afternoon I heard an English actress on the New York
stage pronounce No as if it were spelled NAAO. But after all,
England is the home of the English speech; and I wish that it were
possible for the United States, Canada, Australia, New Zealand,
Capetown and other places to follow in general the best English
spelling and pronunciation. For example, it is certainly better for
Americans to pronounce the word been like the sacred vegetable of
Boston than like the first syllable of the Christian name of Franklin.
In America the most shamefully treated of our five vowels is U,
and the combination of letters EW, which should resemble U in
accuracy, as it now so often does in sin. There should be a distinct
difference between the sound of U and the double O, actually
observable to the naked ear in such words as Duke, Duty, Tutor,
Constitution, Enthusiasm, Tuesday, News.
The way to make this distinction is to remember that the English
language is the only one where the true sound of U is YU; whereas
the Russians, Italians and Germans pronounce U like OO, and the
French differently from any one of these. Just as the Russians
pronounce E as if it were YE, so Americans, when they practice in
secret words like evolution, should visualize a Y in front of the U; it
will help them.
The most popular letter in our alphabet, E, is abominably treated
in such words as cellar, yellow, Philadelphia, where it is so
offensively given the sound of U in “skull”; this is even more common
and still more unpleasant in two useful words, Very and American.
Cultivated English and Americans laugh at the Cockney for
leaving the H silent where it should be heard; but they themselves
are equally and more unpardonably guilty in omitting the H in the
combination Wh. There should be a difference in the pronunciation
of Whine and Wine; yet most cultivated people in both countries talk
about games of Wist, and say Wen, Wich and Wy. Let them heal
themselves before laughing at the Cockney.
The dogletter, R, has a curious fate in American mouths; it is
either unduly accented in such words as Here and Dinner (Middle
West) or it is (East) hitched on to the end of words like idea, and
saw, where it is as awkward as a sailor on horseback. Listen to the
average Yankee when he says “I have no idea of it” and you will see
that he speaks the truth.
XXX
OUR SOUTH AS CURE FOR FLU
The chief reason for my present sojourn at Augusta is the flu,

which attacked me in Connecticut some weeks ago. The American
use of the words “flu” and “grip” is both modern and interesting.
Epidemics of influenza, which seem to cross the ocean from Europe
to America without suffering any sea-change, have been more or
less common since the pilgrims landed at Plymouth. Richard
Hildreth, in his admirable History of the United States, describes
these attacks in the Massachusetts Colony in the seventeenth
century; and it appears from his realistic accounts that they differed
in no respect from recent nation-wide flu epidemics.
If I remember rightly, the word “grip” was not used currently in
America until the epidemic of 1889–1890, which was both severe
and general; it was the subject of constant discussion in the
newspapers, and it was generally believed to be a French
importation, where it was known as la grippe. This in American
became the “grip,” except in certain isolated districts, where it was
called “the la grippe.” But the word, either in its French or English
form, was not commonly used in America until the season of 1889–
1890, when France made a Christmas present of it to the United
States.
The word “flu” had been British slang for some time before it
penetrated America; it was one of the numerous unprofitable things
that our country acquired during the war. In a conversation I had with
the novelist, William De Morgan, in London, in 1911, he casually
used the word “flu,” and for a moment I did not guess its meaning.
Then I saw it was an abbreviation. When the disease crossed the
ocean in 1918, it brought with it its British pet name, which,

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Guy Grant, University of Bedfordshire

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

4.11 Analysis of Systems Dynamics 119 6.13 Transcription Factors 188

chapter 5: Parameter estimation 135

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

Figure 1.1 Biological systems abound at

Sph SphK Malate

GCR1 GPA1 AGB1

Figure 1.3 Analyzing a biological system

Figure 1.4 The size of a network or

(A) Figure 1.5 Biological phenomena are often

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

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

REduCTIOnISM And SYSTEMS BIOLOGY

Figure 1.6 Collecting information is the

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

H2O O2 ABIOTIC STRESS AND BIOTIC RESPONSES

photosynthesis WRKY MYC2 ERF

MVB DREB SA-responsive JA-responsive ET-responsive

nutrients, microbes CYCB

transcription factors hormones CYCD

kinases carbohydrates CDKA

EVEn SIMPLE SYSTEMS CAn COnFuSE uS

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Figure 1.11 Simulation results

different responses. If the effect of Z on TF

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

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

I had an interesting conversation with Bernard Shaw last week.

Men, women, and children are all interested in clothes; there

I look upon horrible dreams as one of the assets of humanity,

Judges xii:6—“Then said they unto him, Say now Shibboleth:

The chief reason for my present sojourn at Augusta is the flu,

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