Cellular Signal Processing An Introduction To The Molecular Mechanisms of Signal Transduction Second Edition 2nd Edition Ebook PDF

Cellular Signal Processing: An
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Preface
All Life is problem solving

Sir Karl R. Popper
All cells process signals: they associate an exogenous stimulus into a “meaning”—
that is, they are able to distinguish between good and bad in order to respond in
an adequate manner. Even for most primitive unicellular organisms, signal pro-
cessing (often called signal transduction) is essential for survival in an unpredict-
able environment. It is understood that a wide variety of diseases including can-
cer, diabetes, dementia, psychoses, and cardiovascular disorders are caused or at
least promoted by disturbances in cellular signal processing, and most therapeutic
drugs, as well as many narcotics, target signaling pathways. Therefore, signal trans-
duction is a subject that ranks among the most rapidly developing fields within
biomedical science.
This book deals with the biochemical mechanisms of cellular signal processing. It is
intended for undergraduate students with a good knowledge of basic biochemistry
and cell biology, and for graduate students in biology, biochemistry, and pharmacol-
ogy, as well as medical students. The book emerged from our scientific work at the
German Cancer Research Center and from a series of lectures we have given at the
University of Heidelberg for many years. Although cell biology textbooks provide ex-
cellent introductions into the field of signal transduction, our students consistently re-
quested a more comprehensive treatment of the subject that, in particular, addressed
evolutionary aspects and questions of medical interest. Moreover, we identified the
need for a textbook that would offer a more complete overview of the field than cur-
rently provided by available books. As such, it may be useful not only for the student
but also for the scientist.
It is currently impossible to depict and describe all the molecular interactions that
occur when a cell receives a signal. In an effort to navigate the middle ground be-
tween incomprehensibility and superficiality, we have confined ourselves to de-
scribing more or less linear signaling cascades that illustrate mechanistic princi-
ples of major signaling pathways, although systems biology is currently integrating
these cascades into networks. One of the hallmarks of this textbook is its presen-
tation of a unifying concept of signal transduction. Cell signaling is traced to a few
simple biochemical switching reactions that link logical operations—mainly per-
formed by protein–protein interactions—with energy-delivering processes of cel-
lular metabolism.
As with the first edition, Chapter 1 deals with the ability of proteins to form a “neural”
network that, together with the genome, resembles a cellular brain. In this network,
each protein acts as a “molecular neuron” that, according to the laws of chemical
thermodynamics and mathematical logic, transforms input signals (environmen-
tal and systemic stimuli) into output signals (cellular behavior facilitating adapta-
tion). According to the second law of thermodynamics, a data-processing apparatus
needs to be supplied with energy. For the protein network, this energy is derived
from a series of exergonic biochemical reactions such as redox processes, GTP and
viii Preface
ATP hydrolysis, protein phosphorylation, and discharge of the membrane potential.

This biochemical arsenal is explained in Chapter 2. As discussed in Chapter 3, the
biochemistry of cellular signal transduction has a long evolutionary history. It was
initiated billions of years ago and, similar to metabolic and genetic mechanisms,
has been conserved during evolution. These basic themes are discussed in more
detail in Chapters 4 through 16. Finally, Chapter 17 places cellular signal process-
ing in the context of systems biology and describes the formation and function of
networks.
In response to our readers, we have updated and reorganized many sections of the
text accordingly. New coverage includes intrinsically disordered proteins, signaling by
non-coding RNAs, new evolutionary concepts of signal transduction, inflammasomes,
regulated necrosis, autophagy, and optogenetics. In addition, the lists of Further
Reading found at the end of each chapter have been entirely revised, providing an
up-to-date guide for exploring the more specialized literature. To this end, we have
focused on the most recent review articles, rather than original publications. Many
of the questions raised today will certainly be answered in the near future, whereas
other problems not yet recognized will become apparent. Nevertheless, our hope for
this new edition of the book, as for the previous one, is that it will be an indispensable
resource for students and scientists who are exploring and working in one of the most
exciting fields in the life sciences.
Acknowledgments
Academic lecturing is a process of giving and receiving, and we are grateful to our
students for their attentive and critical interest and helpful feedback on the first
edition of the book. On this second edition, we are particularly grateful to Dennis
Bray (University of Cambridge), Stefan Rose-John (University of Kiel), Felix Wieland
(University of Heidelberg) and our colleagues from the German Cancer Research
Center Heidelberg: Tobias Dick, Sven Diederichs, Karsten Gülow, Doris Mayer,
and Marcel Schilling for critically reviewing individual chapters in their areas of
interest. We also thank the following reviewers for their suggestions in preparing
this new edition: J. Chloe Bulinski (Columbia University), Ahmet Carhan (Yildirim
Beyazit University), Joseph Eichberg (University of Houston), Laura Frost (Point
Park University), Eric Gauthier (Laurentian University), Kathy Gillen (Kenyon
College), Pascal Lafontant (DePauw University), Boon Chuan Low (National
University of Singapore), Victoria Moore (Elon University), Eric Price (University
of Arizona College of Medicine), and Giovanni Zifarelli (Italian National Research
Council). We kindly acknowledge those who helped on the first edition: Ingrid
Hofmann, Peter Krammer, Frank Rösl (all from the German Cancer Research Center
Heidelberg), Mark A. Lemmon (University of Pennsylvania School of Medicine),
Shigeki Miyamoto (University of Wisconsin, Madison), Bradley J. Stith (University
of Colorado, Denver), Wei-Jen Tang (University of Chicago), and Alexey Veraksa
(University of Massachusetts). In particular, we would like to thank Summers
Scholl, Katie Laurentiev, and Natasha Wolfe at Garland Science for their editorial
and production support and Oxford Designers & Illustrators for their work on the
figures. The editorial team deserves highest appreciation for their professionalism,
helpfulness, and patience.
Preface ix
Instructor Resources Website
The images from Cellular Signal Processing, Second Edition, are available on the
Instructor Site in two convenient formats: PowerPoint® and JPEG. They have been
optimized for display on a computer. The resources may be browsed by individual
chapter and there is a search engine. Figures are searchable by figure number, figure
name, or by keywords used in the figure legend from the book.
Accessible from www.garlandscience.com, the Instructor’s Resource Site requires

registration and access is available only to qualified instructors. To access the
Instructor Resource site, please contact your local sales representative or email
science@garland.com.
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Brief Contents
Preface vii
Chapter 1 The “Brain of the Cell”: Data Processing by Protein Networks 1
Chapter 2 Supplying the Network with Energy: Basic Biochemistry of

Signal Transduction 27
Chapter 3 Evolution of Cellular Data Processing 87
Chapter 4 Basic Equipment: G-Proteins, Second Messengers, and

Protein Kinases 141
Chapter 5 Signal Transduction by Receptors with Seven

Transmembrane Domains 191
Chapter 6 Signal Transduction by Serine/Threonine Kinase-Coupled

Receptors 229
Chapter 7 Signal Transduction by Tyrosine Kinase- and Protein

Phosphatase-Coupled Receptors 249
Chapter 8 Eukaryotic Gene Transcription: The Ultimate Target of

Signal Transduction 291
Chapter 9 Signals Controlling mRNA Translation 329
Chapter 10 Signal Transduction by Small G-Proteins: The Art of

Molecular Targeting 359
Chapter 11 Mitogen-activated Protein Kinase and Nuclear Factor κB

Modules 395
Chapter 12 Regulation of Cell Division 423
Chapter 13 Signal Transduction by Proteolysis, and Programmed

Cell Death 453
xii Brief Contents
Chapter 14 Signal Transduction by Ions 485
Chapter 15 Sensory Signal Processing 543
Chapter 16 Signaling at Synapses: Neurotransmitters and their

Receptors 563
Chapter 17 Putting Together the Pieces: The Approach of Systems

Biology 607
Index 623
Detailed Contents
Chapter 1 The “Brain of the Cell”: 3.3 Signal-controlled membrane transport:

the ancient way to communicate 94
Data Processing by Protein Networks 1 3.4 Sensor-dependent signal processing:
1.1 Metaphors and reductionism: temptations two-component systems 101
and limitations 1 3.5 From vagabonds to societies: “bacterial
1.2 Information and signals 3 hormones”121
1.3 Proteins are binary switches 7 3.6 From bacteria to humans: evolution
1.4 Signal-transducing proteins are “nanoneurons” 9 of signaling mechanisms 126
1.5 Proteins form logical gates and “neural networks”10
1.6 Privacy versus publicity 11 Chapter 4 Basic Equipment:
1.7 Cross talking and network formation 14 G-Proteins, Second Messengers,
1.8 Interaction domains: how the network
is plugged together 17
and Protein Kinases 141
1.9 Generation of signaling patterns 22 4.1 Life is stress 141
4.2 Discovery of intracellular signal transduction 145
Chapter 2 Supplying the Network 4.3 Trimeric G-proteins: coupling of receptors
with the protein network 147
with Energy: Basic Biochemistry 4.4 Downstream of G-proteins: enzymes producing
of Signal Transduction 27 second messengers 153
2.1 No order without work 27 4.5 Guanylate cyclases are not controlled by
2.2 Redox and nitrosylation switches: a balance trimeric G-proteins 176
on a narrow ridge 30 4.6 The next level: protein kinases as sensors
2.3 Switches operated by enzymes that hydrolyze of second messengers 178
energy-rich compounds 34
2.4 GTPase or G-protein switch 36 Chapter 5 Signal Transduction
2.5 ATPase switches 40 by Receptors with Seven
2.6 Protein phosphorylation 47 Transmembrane Domains 191
2.7 Protein acetylation and methylation: tools of
gene regulation and more 58 5.1 An evolutionary model of success 191
2.8 Protein ubiquitylation: more than a signal of 5.2 G-protein-coupled receptors: structure and
protein degradation 61 mode of operation 193
2.9 Mono- and poly(ADP-ribosylation) 69 5.3 Adrenergic receptors: sensors of stress and
2.10 Ion channel switches: how to make use of sympathetic signals 202
electrical charge 71 5.4 Muscarinic acetylcholine receptors are sensors
2.11 Proteolysis switch: protein degradation of parasympathetic signals 209
provides messenger molecules and energy 77 5.5 Stress and the heart: the competition between
2.12 Receptors: how energy-supplying reactions sympathetic and parasympathetic signals 210
are combined with signal transduction 78 5.6 Protease-activated receptors are major players
2.13 Brief summary of experimental standard in blood clotting and inflammation 212
methods for investigation of signaling pathways 81 5.7 Adaptation of G-protein-controlled signaling:
2.14 Model organisms for investigation of cellular a matter of feedback 214
signal processing 83 5.8 Arrestins are multifunctional adaptors for
signaling cross talk 216
Chapter 3 Evolution of Cellular 5.9 Heptahelical receptors in hedgehog and
Wnt signaling pathways 220
Data Processing 87 5.10 Other G-protein-independent heptahelical
3.1 Evolution of biological signal processing 87 receptors: lessons from slime molds
3.2 The RNA world 90 and Homer 225
xiv Detailed Table of Contents
Chapter 6 Signal Transduction by 10.4 Arf and Rab proteins control vesicle
transport383
Serine/Threonine Kinase-Coupled 10.5 Ran, nuclear transport, and mitosis 391
Receptors229
6.1 The principle of oligomerization-driven Chapter 11 Mitogen-activated
signal transduction 229 Protein Kinase and Nuclear Factor
6.2 Ser/Thr-kinases as receptors: transforming
growth factor β receptor family 231
κB Modules 395
6.3 Cytokine receptors: key players in defense 11.1 MAP kinase modules are universal relay
reactions234 stations of eukaryotic signal processing 395
11.2. MAP3 kinases are sensors of MAP kinase
Chapter 7 Signal Transduction by modules400
Tyrosine Kinase- and Protein 11.3 MAP4 kinases and G-proteins: lessons
learned from yeast 404
Phosphatase-Coupled Receptors 249 11.4 Organization of MAP kinase modules by
7.1 Receptor tyrosine kinases 249 scaffold proteins 406
7.2 Receptors associated with tyrosine kinases 268 11.5 Downstream of MAP kinase modules: MAP
7.3 Signal transduction by cell adhesion molecules 280 kinase-activated protein kinases 408
7.4 Protein tyrosine phosphatases and 11.6 Downstream of MAP kinase modules:
phosphatase-coupled receptors 284 transcription factors 410
11.7 NFκB signaling pathway 414
Chapter 8 Eukaryotic Gene
Transcription: The Ultimate Target Chapter 12 Regulation of Cell
of Signal Transduction 291 Division423
12.1 The cell cycle 423
8.1 Initiation of eukaryotic transcription 292
12.2 Cyclins: cell cycle regulators and beyond 425
8.2 Histones, nucleosomes, and chromatin 296
12.3 Cyclin-dependent protein kinases: dual control
8.3 Transcription factors as hormone receptors 306
by phosphorylation and dephosphorylation 426
8.4 Ligand-controlled transcription factors are
12.4 Cyclin-dependent kinase inhibitors: keeping
xenosensors of the toxic stress response 315
the cell cycle under control 428
8.5 Chaperones and peptidyl-prolyl isomerases
12.5 G0 cells, restriction points, and the effect of
prepare signaling proteins for work 318
mitogenic signals 429
8.6 Transcription factors as substrates of
12.6 Retinoblastoma proteins: master regulators of
protein kinases 321
the cell cycle 431
8.7 The hypoxic stress response 323
12.7 Regulation of G2 phase and G2–M transition:
precise like clockwork 433
Chapter 9 Signals Controlling 12.8 Genotoxic stress response: a matter of life
mRNA Translation 329 and death 434
12.9 Phases of mitosis 439
9.1 Eukaryotic mRNA translation: the essentials 329 12.10 Ubiquitin ligase APC/C: giving the beat
9.2 Protein release by the endoplasmic reticulum of mitosis 441
is controlled by G-proteins 331 12.11 Mitotic protein kinases: formation
9.3 Signaling cascades controlling translation 333 of the mitotic spindle 443
9.4 Network for adjustment of cell growth to the 12.12 The spindle assembly checkpoint provides
supply situation 339 a last chance to correct mistakes 445
9.5 The signaling network of non-coding RNAs 355 12.13 Cytokinesis: how a new cell is born 447
12.14 Mitotic exit: characterization in yeast 448
Chapter 10 Signal Transduction
by Small G-Proteins: The Art Chapter 13 Signal Transduction
of Molecular Targeting 359 by Proteolysis, and Programmed
10.1 Ras proteins: generation of order in signal Cell Death 453
transduction359 13.1 Secretase-coupled receptors: generation of
10.2 Other G-proteins of the Ras subfamily: an peptide second messengers 453
unfinished story 369 13.2 Signal-controlled suicide of cells 462
10.3 GTPases of the Rho family are master 13.3 Cancer: a disease of signal processing 476
regulators of the actin cytoskeleton and more 369
Detailed Table of Contents xv
Chapter 14 Signal Transduction 16.3 γ-Aminobutyric acid and glycine receptors

are the masters of inhibitory
by Ions 485 neurotransmission576
14.1 Cation channels: prototypical structures and 16.4 Glutamate receptors are favorites of
gating mechanisms 486 molecular brain research 580
14.2 Voltage-gated Na+ channels: masters of the 16.5 Nitric oxide: a Janus-faced signal molecule 589
action potential 489 16.6 Receptors of purine and pyrimidine
14.3 The multi-talented Epithelial Na+ channels 492 nucleotides: the ATP signal 593
14.4 K+-selective ion channels are regulators of 16.7 Cannabinoid and vanilloid receptors 595
hyperpolarization and osmotic pressure 494 16.8 Opioid receptors 596
14.5 Calcium ions: the most versatile 16.9 Narcotics and drug addiction 597
cellular signals 500
14.6 Downstream of Ca2+ signals 518 Chapter 17 Putting Together the
14.7 Anion channels 535
Pieces: The Approach of Systems
Chapter 15 Sensory Signal Processing543 Biology607
17.1 The whole is greater than the sum of its parts 607
15.1 Taste 543
17.2 Systems biology: origin and focus 607
15.2 Mechanical stimuli: touch and sound 547
17.3 System structure: basic network topologies
15.3 Temperature and pain 550
and properties 608
15.4 Smell 552
17.4 The iterative cycle: laboratory experiments and
15.5 Vision 555
mathematical model development 612
15.6 Sensory adaptation 559
17.5 Problems of quantitative data generation and
mathematical model development 613
Chapter 16 Signaling at Synapses: 17.6 Mathematical modeling of a signaling pathway 614
Neurotransmitters and their 17.7 Synthetic and predictive biology:
Receptors563 the improvement of biological systems 619
16.1 Neurons and synapses 563 Index 623

16.2 Acetylcholine receptors 572
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1
The “Brain of the Cell”:
Data Processing by
Protein Networks
The term signal transduction has become established for the molecular mecha-
nisms by which cells process information transmitted by exogenous or endogenous
stimuli. The goal of signal transduction is to find the response that optimally safe-
guards survival.
In this chapter we shall address the following questions:

●● What is the nature of the cell’s information-processing system?
●● According to which principles does the system work, and what is it able to do?
●● Is the computer a suitable metaphor for cellular signal processing, or would it
be described better in neurological terms?
1.1 Metaphors and reductionism: temptations

and limitations
Living beings are connected inseparably with their environment. Appropriately,
apart from many other qualities, organisms are data-processing or cognitive sys-
tems. On the basis of a program of inherited and acquired information, they attri-
bute a distinct “meaning” to sensory impressions and other exogenous stimuli that
may be understood as “input signals.” This enables them to calculate an “output sig-
nal,” that is, to adjust their behavior, which includes genetic readout, metabolism,
reproduction, shape, and motility, to the given environmental situation. This ability,
which is a condition of survival, is an essential characteristic of life, from primeval
cells to humans.
The processing of large and complex amounts of data requires a network of switch-
ing devices that, as a minimum, make Yes–No decisions according to the basic laws
of mathematical logic and are able to adapt and learn. In biology, such a network
is represented most impressively by the brain with its billions of interacting cells
working as interconnected switching elements. However, the reception and inter-
pretation of signals is not restricted to animals possessing a brain but is a general
property of organisms, even of the most primitive bacteria. What is the data pro-
cessing equipment of a single cell or, so to speak, the “brain of the cell”? It must
be a network of interacting molecules, each resembling a molecular “neuron,” able
to identify the meaning of an input signal and to “calculate” an output signal. This
job is done primarily by proteins, interacting with other macromolecules such as
nucleic acids of the genomic data bank. It is compelling to assume that as far as data
processing is concerned both a network of cells (such as a brain) and a network of
proteins (such as a cell) are working according to the same principles. After all, both
have the same evolutionary background.
2 Chapter 1: The “Brain of the Cell”: Data Processing by Protein Networks
SOCIETY network of individuals

Figure 1.1 Data-processing
networks at different levels of ORGANISM network of cells (for example, neurons)
complexity Technical and biological
data-processing (cognitive) networks CELL network of macromolecules (for example, proteins)
exist at different levels of complexity. PROTEIN network of interacting domains
Even a single protein molecule may
be understood as a data-processing COMPUTER network of microprocessors
network with the individual molecular
domains that make up its three-
dimensional conformation acting as
Whether an analogous conclusion can be drawn for the next higher level of com-
switching elements. Meaningful data
processing requires these switches
plexity, for example, for populations of interacting individuals (Figure 1.1), remains
to interact as directed by the laws of a matter of worldview (Weltanschauung). For some people such a claim would have
mathematical logic. an unbearable biologistic taste, at least when it is extended to human society, where-
as others may remain firm in their conviction of a unifying principle that—emerging
in the course of evolution—dominates living nature.
Still another heuristically tempting metaphor is wandering through the popular and
even the scientific literature: the data-processing network of microprocessors called
a computer. Today it has become fashionable to compare cells, brains, or even or-
ganisms with computers and, vice versa, to denote electronic networks capable of
learning as “neural.” However, this concept, although it has the advantage of clari-
ty, rapidly leads into a cul-de-sac. Biological data processing—even if based on the
same mathematical principles—is certainly more ingenious and sophisticated than
today’s computer technology, and it is still far from clear whether it can ever be in-
terpreted and imitated by a technological approach. So one should treat the com-
puter metaphor with caution, being aware of its narrow limits.
May a similar objection not be raised about the phrase “brain of the cell?”After all,
we are still a long way from understanding the mode of operation of a real brain,
which some people believe (perhaps in an exaggerated opinion of themselves) to be
the most complex data-processing device in the universe. When compared with the
computer metaphor, however, the “brain of the cell” concept has a clear advantage:
it emphasizes the strong resemblance of biological data processing at levels of dif-
ferent complexity. As a consequence, the investigation of cellular data processing is
expected to inspire brain research and vice versa.
Currently, both molecular brain research and molecular cell biology are still more or
less in a phase of hunting and gathering. We are collecting and describing processes,
trying to trace them back in a strictly reductionistic manner to elementary chemical
and physical events. This approach has been extremely successful and is as indis-
pensable as it is highly satisfying; it is also of tremendous importance for medical
applications. Certainly the results obtained thus far provide an estimate of the com-
plexity of biological data processing. However, the expectation that such a method
will lead to a deeper understanding of cellular behavior appears to be as illusory as a
neurobiologist’s anticipation that detailed knowledge of molecular and cellular in-
teractions in the brain would be sufficient to comprehend a systemic property such
as consciousness or even mind, or the conviction of nineteenth century physicists
that knowledge of the locations and impulses of all elementary particles would en-
able a complete prediction of the universe’s future.
The reason for this is that complex systems such as living organisms are always
much more than the sum of their parts. Life is the result of irreversible historical pro-
cesses called evolution and development that continuously create new properties,
which cannot be predicted just by counting and categorizing molecules. Only quite
recently has molecular biology, hitherto the playground of reductionists, become
aware of this problem. As a consequence, strong efforts are being made to extend
molecular research into the area known as systems biology (see Chapter 17). By a
combined approach of bioinformatics, biophysics, bio-engineering, biochemistry,
Information and signals 3
and molecular biology (including genome- and proteome-wide screening studies),

one is trying to translate the language of molecular structures and interactions into
the language of complex systems behavior and the other way around. While there is
no doubt that this methodology will dominate the bioscience field in the twenty-first
century, we have to concede that currently such approaches are still in their infancy.
Thus, lacking a novel intellectual (or even mathematical) concept of the complexity
of living systems, we have to be satisfied by reviewing the present results of our hunt-
ing and gathering of molecules and mechanisms, an endeavor that is not trivial. In
fact, at present the flood of data is rising impressively and alarmingly. However, one
should take care not to embrace new illusions; currently the physiological functions
of no more than 20% of all signal-processing proteins are known. Taking as an exam-
ple a special switching reaction such as protein phosphorylation, we know that at
least one-third, or more than 10,000, of the cellular proteins undergo this chemical
modification, but we understand the physiological relevance of less than 20% of the
phosphorylations occurring in vivo, and this is still in a reductionistic rather than a
systemic manner. Thus, our data collection is far from complete, and many conclu-
sions drawn today may have a rapid use-by date.
Nevertheless, certain basic principles and a couple of biochemical reactions upon

which cellular data processing is based have emerged. They clearly show that the
signal-transducing network primarily consists of proteins communicating with each
other via quite a limited set of noncovalent interactions. These interactions are con-
nected with a dozen or so biochemical reactions delivering the energy required for
data processing, thus maintaining signal intensity and giving the flow of data a defi-
nite direction. The biochemistry of these reactions is surprisingly simple. In fact,
complexity arises from an almost unlimited number of combinations of a few basic
elements rather than from a huge number of complicated structures and reactions.
Summary
●● Data processing is a general property of organisms, being most efficiently
developed in neuronal networks such as the brain. A network of proteins
interacting with each other and with the genome is understood as the “brain”
of a single cell.
●● Both neuronal and molecular networks are assumed to work according to the
same rules, enabling information processing on the basis of mathematical logic.
●● Currently the investigation of biological data processing follows a strictly
reductionistic approach of hunting and gathering, which results in the
construction of (highly artificial) linear cascades of signal-transducing
biochemical reactions. To arrive at a more in-depth understanding, this
approach must be broadened by a comprehensive theory of (biological)
complexity.
1.2 Information and signals

The ability to respond appropriately to environmental stimuli, called sensitivity
(Reizbarkeit) in the older literature, belongs to the basic properties of life according
to the maxim “the lower the degree of uncertainty, the higher the chance to survive.”
Therefore—and to repeat what has already been stated—organisms, from the sim-
plest prokaryotes to humans, are cognitive, or data-processing and learning, systems.
On the molecular level, cognition is based on the unique ability of proteins to pro-
cess data according to logical principles. Their tremendous functional versatility,
their unsurpassed structural flexibility, and their incomparable capability to interact
with each other and with other molecules make them efficient switching elements
response
Figure 1.2 Communication by
signal transmission and signal
transduction A transmitter encodes
a message into a signal, which is message meaning
transmitted to a receiver along a
physicochemical medium. Having encoding SIGNAL decoding
decoded the meaning of the signal,
the receiver transmits a response MEDIUM
signal provided a semantic agreement
exists between both partners; that TRANSMITTER RECEIVER
is, strictly speaking, both master the semantic agreement
same language. In biological systems,
receiver and transmitter may be
individuals, cells, or protein molecules.
The decoding of signals by a cell is of an information-processing molecular network. Proteins are at the same time en-
usually called signal transduction. zymes and constructive elements of the cell.
In other words, the network of enzyme-catalyzed metabolic reactions, as well as the

processes regulating cellular architecture and motility, are inseparably connected
with the data-processing network. In a cell, nothing happens that is not under the
control of this network. This system represents a state of extreme order that—ac-
cording to the second law of thermodynamics—can be generated and maintained
only by continuous energy consumption and on the basis of detailed information
that has to be processed by the cell.
Information is understood as the content of news exchanged between partners—let

us call them transmitters and receivers—aimed at reducing uncertainty and disor-
der. Such an exchange requires information to be represented by symbols such as
letters and words, that can be transmitted via any physicochemical medium, for ex-
ample, sound waves or printed paper (Figure 1.2). Physicochemical entities used
for the exchange of information are called signals.
Information technology distinguishes between analog and digital signals. Analog sig-
nals are omnipresent in music and spoken language. They are characterized by a con-
tinuous encoding of information: within fixed limits, the signal may take on any value
and may be of any length. In contrast, digital signals are generated by discontinuous
encoding of information in the form of short pulses, the intensities of which take on
only a few values. The simplest example of a digital signal is binary encoding with only
two values. In addition, information can be encoded in the frequency, that is, the in-
terval between the individual signal pulses. A classic example is provided by the Morse
alphabet, which also clearly demonstrates the interchangeability of analog and digital
signaling systems. Living systems continuously change between the two systems.
In information technology, signals are mostly electromagnetic impulses and waves,

or sound waves, whereas inter- and intracellular communication preferentially
makes use of molecules and ions (Table 1.1). As a consequence, cells process data
primarily by use of biochemical reactions.
Frequently the symbolic systems are changed in the course of signal transduction:
for instance, when a sensory impression is transformed into an electrochemical
nerve impulse. Such transformations resemble the translation of languages. They
require a code, that is, an instruction of translation by which one symbolic system is
related to another one: for instance, the system of German language to the system of
English language, the system of visual impressions to the system of nerve impulses,
or the system of nucleic acid structure to the system of protein structure.
Information may be encoded in both the intensities and the temporal sequence of
signals, called amplitude- and frequency-dependent modulation. As an example,
a black-and-white sketch is based mainly on amplitude modulation, while a color
Information and signals 5
Table 1.1 Biological signals
Environmental stimuli: sound, light, temperature, touch, taste, and smell;

molecules, xenobiotics, toxic substances, other stress factors
Between organisms: pheromones, gamones, sound, sight, touch, taste, smell
Between cells: systemic mediators such as hormones; local mediators such as

tissue hormones, cytokines, lipid mediators, neurotransmitters, and nitrogen
monoxide; cell surface proteins such as cell adhesion molecules
Within cells: second messengers such as cyclic nucleotides, diacylglycerol,

inositol phosphates, phosphoinositides, Ca2+; interaction domains of proteins
Within protein molecules: conformational changes
picture is based on both amplitude- and frequency-modulated light signals. An anal-

ogous difference is that between noise and music. These examples illustrate that, as
compared with amplitude-dependent modulation, frequency-dependent modula-
tion enables the transmission of much more information, a fact upon which informa-
tion technology critically depends. Both types of modulation are also found in bio-
logical systems. The prototype of a frequency- modulated signal is the nerve impulse.
However, many (perhaps most) biochemical reactions are oscillating as well and may
generate or be regulated by frequency-modulated signals. Thus, frequency-depen-
dent modulation of endogenous signals is expected to be the rule rather than the
exception, and like the brain, a cell may be understood as an ever-oscillating system.
While classical information theory deals primarily with the techniques of encod-
ing and transmission of news, in biology the meaning of signals has top priority.
Since information can be encoded in any physicochemical medium, the meaning
is medium-independent (“the medium is not the message”). Instead, it is read into
the signal on the basis of an inherited and acquired pre-information or program.
By convention, in biology this process of signal decoding by the recipient is called
signal transduction, although signal processing would be a more appropriate term.
From the principle of medium-independent signaling it follows that signals resem-

ble keywords and are principally ambiguous (Figure 1.3): for different receivers, the
same signal may have different meanings. This is an important point, since one can be
tempted to seek the meaning of endogenous biological signals in their chemical struc-
tures, although it is exclusively assigned by the receiver. As an example, let us take the
signaling molecule cyclic adenosine 3’,5’-monophosphate (cAMP). It is interpreted by
many bacteria as a request to activate certain genes (details in Section 3.3.2), whereas
the slime mold Dictyostelium discoideum responds to the same signal by aggregation
into multicellular structures and development into a spore capsule. Numerous and
completely different effects of cAMP occur in vertebrate cells. Another instructive ex-
ample is provided by the vertebrate hormone estradiol that, depending on species
and tissue, exhibits quite different effects (see Figure 1.3). Of course, the reverse holds
true as well: different signals may evoke the same response. For example, in the liver,
the degradation of glycogen is induced by at least seven different hormones.
Although based mainly on biochemical interactions, inter- and intracellular signal trans-
duction follows the same principles as language, where signals (words and sentences)
contain conceptual information only for those who are proficient with the language or
Figure 1.3 Signals are ambiguous

(the medium is not the
message) As the scent of a medium-
sized animal has a deterrent effect
on small animals but attracts a
larger animal, biological signals
have completely different meanings
depending on the species, the tissue
type, and the physiological context,
that is, on the program of signal prokaryotes transcriptional co-activator
decoding. cAMP D. discoideum attractant and hormone
vertebrates second messenger with various meanings
uterus proliferation, differentiation

vagina epithelial keratinization
estradiol brain control of hormone biosynthesis
oviduct synthesis of ovalbumin and other proteins
liver synthesis of vitellogenin
who possess the program of decoding. A comparison between language and chemical
signal transduction immediately clarifies the analogy between the systems (Figure 1.4).
Moreover, it tells us that there is a direct causal relationship between the cellular and
the social levels of complexity: on the one hand language is the result of elementary
molecular events occurring in neurons (bottom-up effect); on the other hand, emotion-
ally charged sentences inevitably have an impact on the biochemistry of cells, including
the activity of genes (top-down effect). Such a reciprocal resemblance is a characteristic
feature of living systems. It will be discussed in more detail in Chapter 17.
Summary
●● Organisms are cognitive or information-processing systems. On the basis
of inherited and acquired knowledge (the program), they relate a certain
meaning to an environmental stimulus that is transmitted as a signal, or a
distinct modulation of a physicochemical medium.
●● Signals per se are meaningless. Their interpretation depends solely on the
receiver’s program and the physiological context. Therefore, a signal is
ambiguous: it may have different meanings depending on the recipients and
the given situation.
“SPEAKER” “LISTENER”
chemical
signal
acoustic word structure RECEPTION
TRANSMISSION structure word
Figure 1.4 Resemblance between signal
acoustic and chemical signal
transmission In both cases the ENCODING meaning term term meaning DECODING
speaker’s data bank (memory)
constructs an image of its environment
that is equipped with a meaning and REMEMBERING image image image image LEARNING
transmitted as a signal (molecule
or word) to a listener, who decodes
the signal, interpreting its meaning memory memory
by means of his signal-processing
apparatus, that is, asking his memory
store. RESPONSE
Proteins are binary switches 7
1.3 Proteins are binary switches

Information-processing systems are made up of interconnected switching elements
or elementary calculators that transform an input signal into an output signal ac-
cording to the laws of mathematical logic. In the simplest form, a switch represents
the binary values 0 (OFF) and 1 (ON) (Figure 1.5). It is a special property of proteins
to exist at least in two different states: an enzyme, for example, is either inactive
(state 0) or active (state 1). The states differ in their three-dimensional structure or
conformation. Any protein molecule may be considered, therefore, to be an elemen-
tary signal-processing unit. Input signals are influences that change the equilibrium
between 0 and 1 and thus the functional state. As a rule such changes are caused by
chemical ligands, but depending on the type of protein, changes may also be caused
by other stimuli such as pressure, light, and temperature. The output signal is the
effect resulting from the altered function of the protein, which in turn is a result of
an altered conformation. For instance, an enzyme transforms the input signal “sub-
strate concentration” into the output signal “product concentration.”
For most enzymes, substrate concentration is not the only input signal but their ac-
tivities are controlled and fine-tuned by numerous activators and inhibitors that act
as additional input signals. This regulatory principle also holds true for other pro-
teins. How such additional input signals manipulate the protein switch is explained
by the theory of allostery. It is based on the concept of regulatory protein domains,
which are not identical with the active center but, nevertheless, influence protein
function via long-range effects on the protein’s three-dimensional structure, the
conformation. In its most concise form (as originally formulated by Monod, Wyman,
and Changeux in the early 1960s), the theory assumes a protein to exist in two dif-
ferent conformations, being in equilibrium and differing in their activities as well as
their affinities for regulatory factors, which we may call input signals S (Figure 1.6).
To make clear that the allosteric effect is a binary switching event, we shall replace
the historical terms T (tense) and R (relaxed) by 0 (=T) and 1 (=R).
Let us assume S to be a stimulatory signal or, in pharmacological terms, an agonist.

In the absence of S, the protein may be assumed to be mostly in conformation 0: the
switch would be in the OFF position. In the terminology of chemical thermodynam-
ics, conformation 0 is said to have a low standard free energy. This means that the
transition from 0 to 1 is an endergonic reaction that does not occur spontaneously
but requires a supply of energy. When S interacts with the regulatory domain of the
protein, the equilibrium is shifted to conformation 1: the switch is turned into the ON Figure 1.5 Proteins as binary
position, provided the signal molecule S has a higher affinity for 1 than for 0 and the switches Most proteins exist in
energy released upon binding of S is sufficient to push the conformational change. at least two different functional
states (here called states 0 and 1)
The theory also explains the effect of an inhibitory signal or antagonist. It has a that are represented by different
higher affinity for 0 than for 1 and arrests the switch in the OFF position. Frequently conformations. In state 0 the protein
one is dealing with mixed agonists–antagonists that, depending on the concentra- is assumed to be inactive (in the
tion, act either as activators or as inhibitors. closed or off position) because in this
conformation the active site is blocked
by an intramolecular interaction. An
active
site
“input signal” is any influence that
transforms or switches one state into
0 (off) the other. The conformational change
thus induced releases the protein
from autoinhibition, resulting in an
conformational
INPUT change “output signal” generated by the
SIGNALS active site (another input signal may
trigger the reverse 1 → 0 switch). This
1 (on) elementary data-processing unit is an
oversimplification because in the cell
proteins may exist in much more than
two different states or conformations
OUTPUT SIGNAL
(see, for instance, Section 1.8.5).
functional regulatory
Figure 1.6 Allosteric switching domain domain
of protein function A protein
with spatially separated regulatory 0 (off) INPUT
and functional (catalytic) domains SIGNALS
is thought to exist in at least two
conformations, 0 and 1, that are
allosteric equilibrium
in an allosteric equilibrium. An
agonistic input signal stabilizes
conformation 1, thus shifting the 1 (on)
equilibrium downward. In contrast,
an antagonistic input signal would
stabilize conformation 0, shifting the
OUTPUT SIGNAL
equilibrium upward (not shown).
Agonistic and antagonistic signaling factors are either small molecules and envi-
ronmental stimuli or proteins that interact with their target protein via specific do-
mains. These domains are amino acid sequences that are able to recognize and to
bind complementary sequences of their own (homotypically) or of a different struc-
ture (heterotypically). They will be discussed in more detail in Section 1.8. Such pro-
tein–protein interactions occur according to the principles of allosteric regulation.
The interaction of a signaling molecule with a protein may be either covalent or non-
covalent. Protein phosphorylation and other post-translational modifications repre-
sent covalent binding, while noncovalent binding is typical for the interaction of a
hormone with its receptor or for most protein–protein interactions.
To return the switch back to 0, the agonistic signal S has to be removed from the
binding equilibrium, a process known as signal extinction. A dilution or chemical
inactivation of S is sufficient to reverse a noncovalent interaction, whereas a cova-
lent modification requires a chemical cleavage, which as a rule has to be catalyzed
by a specific enzyme (Figure 1.7).
When a protein consists of several subunits, the theory of allostery predicts coop-
erativity. Accordingly, the interaction of one subunit with the signaling molecule
either facilitates (positive cooperativity) or hinders (negative cooperativity) the
(A)
noncovalent
cAMP
dilution
enzymatic cleavage
Figure 1.7 Interactions of signaling
molecules with proteins (A) Binding
(B)
of cyclic AMP (cAMP) as an example of –
covalent phosphate donor (ATP) O
a noncovalent interaction. The cAMP
signal is extinguished by dilution and –
phosphorylating O P O
by enzymatic degradation, driving the enzyme (kinase)
O
reaction in the reverse direction. In an
analogous manner, proteins interact OH
with each other. (B) Phosphorylation as
an example of a covalent interaction dephosphorylating
or post-translational modification. enzyme (phosphatase)
Both the forward and reverse reactions
require enzymatic catalysis. phosphate
Signal-transducing proteins are “nanoneurons” 9
binding of additional signaling molecules, resulting in conformational changes of output

the other subunits. A cooperative effect is indicated by a sigmoidal curve when the signal
activity of the protein, or the output signal (for instance, measured as enzymatic B
reaction rate), is drawn in relation to the ligand concentration, or the input sig-
nal S. Signal-transducing systems with a sigmoidal characteristic are resistant to
low irregular signal intensities called noise, which is feared as a disruptive factor A
in information technology. In other words, cooperative proteins possess a built-
in noise filter (Figure 1.8). In contrast, proteins without quaternary structure
mostly exhibit linear or hyperbolic kinetics, and thus they lack a noise filter. This
may be one major reason that signal-transducing proteins mostly consist of sev-
eral subunits forming oligomeric structures and that, in addition, they form com- input
plexes with other signaling proteins. Such signal-processing particles have been noise
signal
filter
called “signalosomes” (examples will be found throughout this book). Moreover, a
system with a sigmoidal characteristic operates like an on–off switch, whereas sys-
tems with linear or hyperbolic kinetics rather work as accelerators or brakes (see Figure 1.8 Noise suppression by a
Section 1.9). sigmoidal characteristic of signal
transmission With sigmoidal kinetics
(curve A), a significant output signal
Most signaling proteins form not only oligomers but, moreover, are expressed in
is produced only when the input
several subtypes or isoforms that result from individual genes, from genes with
signal surpasses a certain value. Such
alternative promoters, and from post-transcriptional modifications such as alter-
a system has a built-in noise filter and
native splicing of pre-mRNA. Such isoforms may be restricted to individual tissues resembles a switch with first trigger
and cell types and may exhibit different functions. In addition, they provide the sig- pressure. In contrast, a system with
nal-processing apparatus with a high degree of redundancy, which in technology hyperbolic characteristics (curve B)
is considered to be a feature of superior design since it considerably diminishes the responds to very weak input signals
susceptibility to faults (see also Chapter 17). including accidental noise. It resembles
a rotary switch or an accelerator pedal.
The theory of allostery was originally developed to explain the cooperative behavior
of proteins with quaternary structures. However, it is not restricted to such proteins
(as is frequently stated in textbooks) but applies to any protein with separated reg-
ulatory and catalytic domains, though in the absence of a quaternary structure the
allosteric interaction is not easily recognized from the kinetics but has to be proven
by costly structural analyses.
Summary
●● Proteins may be looked upon as switching elements of a data-processing
molecular network.
●● Switching is due to a conformational change induced by an input signal. As a
result, the protein function representing the output signal is modulated.
●● The conformational change results from an intra- or intermolecular allosteric
interaction between a regulatory domain (receiving the input signal) and a
functional domain (transmitting the output signal).
●● In proteins with a quaternary structure, cooperative allosteric interactions
provide a noise filter.
1.4 Signal-transducing proteins are “nanoneurons”

The cells of the brain are specialized for information processing. The same holds
true for the proteins of cellular signal transduction. They differ from metabolic en-
zymes or architectural proteins as neurons differ from liver or skin cells. For such
signal-transducing proteins, the concept of working as simple binary switches de-
scribes a borderline case, since most of them are controlled by much more than one
input signal.
In fact, in their capability to convert numerous input signals (or allosteric effectors)
into an output signal or even digital into analog signals, such proteins—albeit on a
lower level of complexity—resemble neurons, where a large number of dendritic
NEURON
Figure 1.9 Proteins as
“nanoneurons” A neuron
input
converts numerous input signals signals
(nerve impulses) received at the output
signal
dendrites into an output signal axon and synapse
transmitted at the axonal synapse.
In an analogous manner, a protein
dendrites
receives input signals at its regulatory
or interaction domain that, through
a conformational change, become PROTEIN regulatory catalytic
converted into an output signal domain domain
released by a catalytic or functional
domain.
input output
signals signal
conformational
change
synapses serve as signaling input terminals and the axonal synapse acts as an output
terminal. In signal-transducing proteins, such synaptic contacts are replaced by struc-
tural domains. As a rule, the input terminals are binding sites or interaction domains
for allosteric regulators, whereas the functional domain (for instance, the catalytic
center of an enzyme) serves as the signaling output terminal (Figure 1.9).
Since function strictly depends on the three-dimensional structure of a protein, the

conversion of input signals into the output signal occurs through (mostly allosteric)
conformational changes acting in either an additive, synergistic (more than addi-
tive), or antagonistic manner. As will be explained in Section 1.8, regulatory pro-
tein domains react not only with input signals from the outside but also with each
other. These intramolecular effects are an important condition of signal conversion
because they determine the algorithm of the protein calculator. Their elucidation
ranks among the most important and most difficult tasks of current biochemistry
and structural biology.
Summary
●● In general, signal-transducing proteins have more than one receiver site for
regulatory input signals.
●● In their ability to integrate various input signals and to calculate an output
signal, they resemble neurons, albeit at a lower scale of complexity.
1.5 Proteins form logical gates and “neural networks”

Switches—even simple binary ones—may be used to carry out fundamental logical
operations of the type NOT, AND, OR, and NOR according to the rules of Boolean
algebra. These operations are sufficient to process any kind of logical information.
The corresponding circuits, called logical gates, are the elementary units of technical
data-processing networks that, as already mentioned, resemble the nervous system
to a certain extent. Because these technical devices are able to adapt and to learn,
they are called neural networks, with the idea that someday they may imitate living
systems, including intelligent behavior (artificial intelligence). Such a concept was
formulated initially in the 1940s, when it was shown theoretically that a switching
device of a few simplified and strongly idealized neurons, called “McCulloch–Pitts
Privacy versus publicity 11
neurons,” could perform logical operations. When they are understood as cellular NOT 1 not S 0
“nanoneurons”, proteins are also expected to operate as logical gates and, like mo-
lecular McCulloch–Pitts neurons, assemble to form a data-processing network, or S1
the “brain of the cell” (Figure 1.10). AND and 1
S2
It should be noted that like the concept of binary protein switches, the rigid Yes–No
decisions of Boolean logic represent a borderline case that cannot fully describe bi- OR either S1 1 or S2 1
ological data processing. Instead, so-called fuzzy logic, based on the mathematical
S1 S1
theory of fuzzy sets, is more suited to explain decision and regulatory processes oc- 1 but 0
NOR
curring in response to the incomplete, imprecise, and even contradictory informa- not
tion an organism typically receives from its environment. S2
For the brain, the actual state of function of its neuronal network resembles what is Figure 1.10 Proteins as logical
called random access memory (RAM) in computer technology. The corresponding gates The active protein (producing
memory store of a cell is the functional state of its protein network. Like a brain, it uses an output signal) is depicted in teal
its genetic and acquired program to construct an image of the surroundings (for a (state 1), and the inactive protein is
unicellular organism or for a sensory cell, it is the environment, and for a tissue cell, it shown in gray (state 0). A protein
would be the internal milieu of the body). This enables the cell to calculate a response working as a NOT gate does not
necessary for survival. Therefore, the idea of a protein network representing some- transmit an output when it receives
thing like the “brain of the cell” appears to be not too far-fetched, though one should an input signal S. An AND gate
refrain as much as possible from anthropomorphic metaphors, keeping in mind that a produces an output signal only when
single cell does not “think.” Moreover, the images constructed by the protein network it receives two input signals S1 and S2
are necessarily incomplete, because only those signals for which the network is phylo- simultaneously (so-called coincidence
genetically and ontogenetically programmed are recognized and processed (though detector). An OR gate responds either
this also holds true for our brain!). to S1 or to S2. To produce an output
signal, a NOR gate must receive only
A more questionable or even dangerous metaphor is that of the “computer of the signal S1 but not signal S2.
cell.” Albeit it certainly has the advantage of clarity and for this reason alone it is
used at times in this book: for instance, when referring to switching elements or
random access memories. Although information technology tries very hard to im-
itate biological data processing by neural networks, the results are still rather mea-
ger since certain principles of biological systems either are not fully understood or
are realized only with difficulty. Thus the hardware of protein networks, in contrast
to customary electronic networks, is not irreversibly wired but self-organizes con-
tinuously into ever-changing patterns depending on the task and the physiological
context. This self-patterning is a direct consequence of a characteristic property of
proteins, which is the ability to interact with each other and with other signaling
molecules at any place in the cell. Thus, data-processing protein networks are con-
tinuously reorganized both spatially and temporally.
Summary
●● Interacting proteins form logical NOT, AND, OR, and NOR gates, enabling the
cell to process any kind of information.
●● When the extreme flexibility and complexity of cellular data processing is
considered, the computer metaphor appears to be questionable. It would be
more appropriate to speak of the “brain of the cell.”
1.6 Privacy versus publicity

Signals that transmit news may have a private character, where they address a dis-
crete partner, or they may be directed at the public (Figure 1.11). This principle also
holds true for inter- and intracellular signal transduction. As shown in Figure 1.12,
signaling between cells may range from highly public to highly private. Thus, the
endocrine system works via public long-range effects, while the nervous system op-
erates mainly via private short-range (para- and autocrine) effects. The highest level
Figure 1.11 Private versus public

signaling (Adapted from Sempe
JJ [1968] Volltreffer. Deutscher
Taschenbuch-Verlag.)
!
CE
EN
SIL
of privacy is reached when cells communicate via membrane-bound signaling mol-
ecules (juxtacrine signaling).
Figure 1.12 Different pathways of
In an analogous way, proteins may interact with each other in a widespread or
signal transmission between cells
and molecules Long-range signaling in a strictly targeted manner. Targeted short-range effects that maintain priva-
between cells is called endocrine when cy are due to interaction domains, working like electronic contacts, while for
the signal molecule is transported widespread long-range effects, an enzymatically active protein produces a large
by the bloodstream (typical for amount of diffusible messenger molecules that interact, either covalently or non-
hormones), paracrine when the signal covalently, with a high number of remote partner proteins (publicity). A char-
diffuses between neighboring cells acteristic example of long-range effects is provided by second messengers such
across the extracellular matrix (typical as cAMP or calcium ions, which are released in large amounts and may diffuse
for neurotransmitters and many throughout the cytoplasm upon stimulation of a few transmembrane receptors
so-called tissue hormones or local (see Chapter 3).
mediators), and autocrine when the
signal re-acts on the transmitter cell
(typical for neurotransmission and
INTERCELLULAR INTERMOLECULAR
developmental processes). Short-range
signaling through a direct contact ENDOCRINE SECOND MESSENGER
between cells via membrane-bound cytoplasm
signaling proteins is called juxtacrine bloodstream
(typical for developmental processes).
While endocrine signaling has a public protein 1 protein 2
character, para-, auto-, and juxtacrine
signals are more private. Endocrine
signals find their intracellular PARACRINE PHOSPHORYLATION
counterparts in signal molecules (such
as second messengers), which are
autocrine
produced by an enzymatically active autophosphorylation
protein providing intermolecular long-
range signaling by diffusing through protein 1 protein 2
the cytoplasm. The more private para
and autocrine signaling resembles
interactions that depend on a close
encounter between the proteins. JUXTACRINE DIRECT CONTACT
Protein phosphorylation provides an
illustrative example. A direct signaling
contact between proteins resembles protein 1 protein 2
juxtacrine signaling. The signals are
symbolized by teal triangles.
Privacy versus publicity 13
Depending on the context, signaling through second messengers may have also
a more private character. In fact, short-range interactions in subcellular networks
(spatial privacy) are facilitated by potent mechanisms of signal extinction that re-
strict a signal to a very limited area of the cell. Moreover, certain proteins that are
specialized to act as adaptors or scaffolds may bring interacting proteins into con-
tact or dock them only at specific cellular sites (see Section 1.8; for some illustrative
examples see Sections 4.6.1 and 11.4).
Another hallmark of biological signaling is temporal transitoriness. A neuronal

signal, for instance, is short-lived in order to avoid overstraining the system. Long-
lasting effects require, therefore, an oscillating signal that, at the same time, enables
frequency-dependent modulation. This is a typical feature of signaling in the ner-
vous system. Intracellular signal processing by protein networks is dominated by
the same rule. Here a wide variety of inactivating mechanisms guarantees transi-
toriness. Moreover, signal-generating and signal-extinguishing proteins frequently
are coupled to modular complexes that fulfill the conditions of molecular oscillators
(see Section 1.9.3). Therefore, a wavelike pattern and a frequency-dependent mod-
ulation of intracellular signals may be assumed to be the rule rather than the excep-
tion (for details, see Sections 4.6.1, 11.6, and 14.5.4).
Summary
●● By interacting with each other and with other cellular constituents, proteins
form a neural network of logical gates. Network formation is based on the
property of proteins to communicate with each other by both short- and long-
range interactions (thus resembling organisms).
●● Short-range effects are due to direct contacts (using specific contact or
binding domains), while long-range interactions are transmitted by signaling
molecules. Thus, subcellular signal processing resembles both widespread
hormonal signaling and targeted neuronal signaling.
●● Both neuronal and subcellular signal processing are dominated by the
same principles: spatial privacy, temporal transitoriness, redundancy of
the components, and frequency-dependent modulation of the signals
(Sidebar 1.1).
Sidebar 1.1 Trivial and nontrivial calculators ta-processing apparatus requires, therefore, a certain de-
The physicist Heinz von Foerster has clearly distinguished gree of nontriviality to enable the organism to balance
the differences between trivial and nontrivial calculating on the narrow ridge between reliability and chaos and,
machines. A trivial machine such as an abacus uses a fixed thus, to make meaningful decisions. This holds true for
algorithm, always converting a given input value into the proteins: each “arithmetical operation” leaves a track in
same output value: it is reliable and predictable but unable the molecular conformation, which influences the forth-
to adapt and to learn. In contrast, a nontrivial machine coming operations and renders proteins adaptable if they
uses an adaptable algorithm depending on the previous possess a structural memory. Since one never knows the
operations. previous operations with certainty, it is impossible to
precisely predict the function of a protein. This nontriv-
It is able to learn and has a memory. In the extreme case ial behavior of proteins is the basis of all biological data
this means, however, that a nontrivial machine reacts processing, culminating in the abilities of the human
chaotically, unpredictably, and unreliably. Since living brain. Von Foerster has emphasized that any kind of edu-
systems have to survive in an unpredictable environment, cation—but in particular military drill—is aimed at a re-
they need to be adaptable and be able to learn. Their da- duction of nontriviality.
1.7 Cross talking and network formation

The nervous system is an extremely complex network of cells communicating via
a large variety of para-, auto-, and juxtacrine interactions. This organization, being
mandatory for a data-processing system, finds its counterpart at the subcellular lev-
el in the network of signal-transducing proteins, albeit with a lower degree of com-
plexity.
Previously, only linear pathways of signal transduction connecting the cellular periph-
ery with the metabolic and genetic apparatus could be analyzed. It became clear, how-
ever, that the picture thus obtained resembled an extreme oversimplification because
in reality such pathways were found to be interconnected by a phenomenon called
“signaling cross talk.” In fact, this term is nothing but a synonym for signal processing
by a protein network. It is now generally accepted that any signal received by a cell acti-
vates a substantial part of the data-processing protein network rather than stimulating
just a simple sequence of a few biochemical reactions, a concept that, for an in-depth
investigation, imperatively requires novel approaches such as that of systems biology
(see Chapter 17). The situation closely resembles data processing in the brain, where a
single sensory input induces an extended (diffuse) activation pattern rather than stim-
ulating just a small group of specialized neurons (Figure 1.13).
Impressive microscopic photographs and three-dimensional models showing the

beauty and complexity of the neuronal network in the brain have given a vivid impres-
sion of the cross talk between nerve cells. For molecules, such a visualization is not yet
possible. Instead we have to fall back on more indirect evidence. We know, for instance,
that cytoskeletal and membrane structures play a key role in support of the signal-pro-
cessing protein network. Thus, the complexity of such hardware, or scaffolding, may
reflect the complexity of the “cellular brain” to a certain extent (Figure 1.14).
As far as teaching is concerned, signaling cross talk creates a problem because for
the sake of clarity it is impossible to depict and describe all the interactions that
occur when a cell receives a signal (Figure 1.15). So in textbooks—including this
one—still more or less linear, artificial signaling cascades are presented. However,
the reader should always keep in mind that this is an oversimplification, illustrating
mechanistic principles rather than the complex reality.
1.7.1 Network biology

A new discipline of theoretical biology known as network biology is emerging that
deals with the rules and laws dominating the formation and function of molecu-
Figure 1.13 Diffuse signal

processing by the human brain In
the brain, the processing of even
rather simple sensory inputs results
in extended and diffuse excitation
patterns involving a large number of
neurons and developing on the basis
of apparently chaotic background
activity. At the molecular level, an hearing words reading words
analogous situation has to be assumed
for cellular signal processing. The
excitation patterns were visualized
by a method measuring the blood
circulation. Albeit providing more
details, advanced techniques of
imaging principally have confirmed this
result. (Adapted with modifications
from Fischbach GD [1992] Sci Am
267:48–57.) speaking words generating words
Cross talking and network formation 15
Figure 1.14 The cytoskeleton:

hardware support of the data-
processing protein network The
photographs show the extremely
complex structure of cytoskeletal
fibers in the neighborhood of a
mitochondrion (A) and in the border
zone between cytoplasm and nucleus
(B). (A, adapted from Darnell JE, Lodish
HF & Baltimore D [1990] Molecular
Cell Biology, 2nd ed. Scientific
(A) (B)
1 μm 1 μm
American Books. B, adapted from
Penman S [1995] Proc Natl Acad Sci
USA 92:5251–5253.)
lar networks. Combining molecular biology, biophysics, and mathematics, this re-
search has focused on five types of network: metabolic, genetic, transcription factor,
protein interaction, and protein phosphorylation. These approaches are strongly
facilitated by novel high-throughput techniques that use cDNA microarrays, protein
chips, and other automated methods to allow genome- and proteome-wide screen-
ing. Moreover, a conceptual framework has been developed to characterize different
types of network (see Chapter 17).
TM4SF Endonexin
? 0
Integrins
+ +
+
+ +
+ FAK Caveolin-1
+ + + + +
PTEN + Src Grb7 RPTK Fyn
+ + + + +
+
+ – + + + + + + +
Graf + +
+
P13K1a ASAP1 p190RhoGAP Cas Paxillin gamma PLC SHC

– – + + +
+ – + +
+
ILK + ARF Rho + Crk + PKL/GIT Grb2
?
+ + + + +
+
? AKT/PKB ? AND-34 DOCK180 Abl C3G PIX/COOL SOS
+ +
+ + + + + +
+
Ral R-Ras Cdo42 Rap1 Rac Ras
+ + + + + Figure 1.15 The integrin signaling
+ + + +
network The figure shows the
ACK WASP MLK-3 PAK B-Raf Raf-1 complex signal processing network
? + + + + + activated by a single membrane
+
A-Adinin Talin + MKK 4 MEK
receptor (integrin) that interacts with
two different extracellular signals.
0 0 ? It must be emphasized that the
Arp2/3 + – + sketch depicts only a small fraction
? 0
of what is expected to happen in
reality. The situation is exemplary
Zyxin Vinculin ROCK JNK ERK
?
for most signal-processing events.
? – + + +
+ ? 0 + (Adapted from Martin KH, Slack JK,
VASP MLCP MLCK Calpain Boerner SA, Martin CC & Parsons JT.
+ – + Integrin signaling pathway. Sci Signal
(connection map in the database of
actin RLC
cell signaling).)
Using simple organisms such as yeast, one can generate computerized graphs that
show an illustrative, albeit rough, survey of intermolecular crosstalk and allow the
discovery of hitherto-unknown interactions, at least on paper. There is no doubt that
a more systematic understanding of these networks is urgently needed. However,
network biology is still in its infancy, particularly because of the difficulty in uncov-
ering the physiological role of the interactions described. Therefore, one must wait
and see whether this new discipline will significantly broaden our understanding of
cellular phenomena, especially of signal processing, or—remaining on a descriptive
level—if it will only provide a new mathematical formalism. In the following section,
as well as in Chapter 17, the reader will be able to glimpse the problems network
biology is facing.
1.7.2 Some remarks on the complexity of the “cellular brain”

When compared with the size of a genome, the number of genes encoding signaling
proteins is rather modest. Thus, analysis of the human genome has shown that, of the
approximately 30,000 genes, about 1500 encode signal receptors, 500 encode protein
kinases, 150 encode protein phosphatases, and 1500 encode transcription factors,
just to mention some of the most common switching elements of the data-processing
protein network. Most of these genes contain several (up to 200) exons, which means
that transcribed pre-mRNA probably undergoes alternative splicing. As a rule, the
proteins encoded by such splice variants exhibit different properties such as ligand
affinities, intracellular distributions, enzymatic activities, and stabilities. Arbitrarily
assuming at least three different splice variants are produced per gene, one arrives at
4500 different signal receptors, 1500 protein kinases, 450 phosphatases, and at least
4500 transcription factors.
Each of these proteins is expected to undergo covalent post-translational mod-

ifications and so its properties are changed further. Let us again assume that
three different modifications per protein occur on average (which certainly is
an understatement). These modifications produce 23 = 8 different states, since
each modification exists in two states, either present or absent. This calculation
increases the number of receptor variants to 36,000, kinase variants to 12,000,
phosphatase variants to 3600, and transcription factor variants to 36,000, thus
greatly outnumbering the total number of genes. The degree of complexity is fur-
thermore enlarged dramatically by the understanding that most signal-process-
ing proteins exist as homo- and hetero-oligomers rather than as monomers and
that the number of functional states of a network increases exponentially with
the number of the components. In fact, in a single cell the number of dynamic
states generated by the interactions between signal-processing proteins must be
astronomically high.
It must be emphasized, however, that in a given tissue cell only a fraction of these
variants becomes realized. The pattern of active signaling proteins thus generated
changes continuously, depending on the state of differentiation and the actual phys-
iological context. This is what we have called the rearrangement of the hardware
components and actual state of the random access memory. The overwhelming
complexity of the “cellular brain” indicates that our efforts to understand life are still
in their infancy.
Summary
●● The data-processing network of the cell is based on chemical interactions or
crosstalking between the components. Therefore, a single signal received by
a cell evokes a diffuse excitation pattern rather than activating one or a few
signaling pathways.
●● As yet, the extreme complexity and flexibility of such networks prevent a more
in-depth analysis of their physiological functions.
Interaction domains: how the network is plugged together 17
1.8 Interaction domains: how the network is plugged

together
Proteins are assembled into highly organized signal-transducing complexes and da-
ta-processing networks. This occurs on demand in a fully reversible manner. How
is this achieved? The original concept of proteins as freely diffusible molecules en-
countering each other more or less by chance is considered to be outdated today.
Owing to the extremely high concentration of macromolecules (known as macro-
molecular crowding), the interior of a cell needs to be viewed as a semi-solid medi-
um in which free diffusion would be far too slow for life processes. In addition, nei-
ther a precise arrangement nor a controlled interaction of the components would
be possible. However, both are mandatory for cellular data processing. Thus, protein
interactions must be brought about by other more specific and more targeted pro-
cesses.
1.8.1 Protein modules

Complex formation is a direct consequence of a characteristic structural feature
known as the modularity of proteins. Proteins are composed of defined amino acid
sequences or modules according to a unit construction system. Generally one may
distinguish between functional and interaction modules. A functional module is,
for example, the catalytic domain of an enzyme, whereas interaction modules serve
as contact sites for all kinds of allosteric regulators—including proteins with com-
plementary contact modules, diffusible signaling molecules such as second mes-
sengers, and systemic and environmental factors—as well as for cellular structures.
Interaction modules guarantee relatively stable (though mostly noncovalent) bind-
ing between the partner molecules. In signal-transducing proteins, the interaction
modules are identical with the regulatory domains that serve as terminals of input
signals, while functional modules are the catalytic domains that generate output
signals (see Figures 1.5, 1.6, and 1.8). As a rule, signal transducing proteins have
many more interaction modules than other proteins such as metabolic enzymes.
In the course of evolution, the protein modules were recombined into new patterns
by genetic rearrangements. Accordingly, innovations in signal processing (resulting
in novel properties of the organism) are brought about by unique combinations of
existing building blocks rather than by invention of entirely new protein structures.
This mechanism of evolvability is a major driving force of complexity. By means of
such a combinatorial strategy, cells establish the astronomically large number of
protein contacts by using relatively few interaction domains.
The pattern of protein domains represents something like a signaling syntax, and
the highly organized multimodular structures and multiprotein complexes thus
formed resemble microprocessors to a certain extent. Nevertheless, and in contrast
to a computer, proteins are not firmly interconnected but are assembled and dis-
assembled upon demand by energy-consuming reactions. This reversible wiring
is promoted, in particular, by covalent post-translational modifications of protein
modules, generating ad hoc new sites for inter- and intramolecular contacts that
immediately become untied when they are no longer needed. By this means, new
interaction patterns are continuously formed between proteins, just as one might
expect for an adaptable and educable neural network. The cooperation of the indi-
vidual domains in such patterns lends protein interactions the necessary precision.
The principles of domain interactions are depicted in Figure 1.16, while in Table 1.2,
selected interaction domains are summarized and arranged according to the rec-
ognition sites of their interaction partners. The first group includes domains that
recognize short peptide sequences. The domains of the second group interact with
peptide sequences containing covalent post-translational modifications due for in-
stance to phosphorylation, acetylation, methylation, and ubiquitylation. Interaction
domains not listed in the table include binding sites for extra- and intracellular sig-
nal molecules, found in receptors and in many other signal transducing proteins, as
protein 1 protein 2
Figure 1.16 Interaction
domains The figure shows interaction
domains of proteins that are binding
sites for other protein molecules
carrying a specific recognition
signal. To the left, an interaction
domain is depicted that recognizes
a heterotypical signal, for instance, a interaction post-translational
domain modification
post-translational protein modification.
In the middle, a heterotypical
interaction is shown occurring in the
same protein molecule. The scheme
to the right shows a homotypical
interaction between two identical
interaction domains. Other interaction
domains recognize low molecular mass
messenger molecules, specific nucleic
acid sequences, and membrane lipids. heterotypical intramolecular homotypical
Receptors exhibit an enormous variety
of interaction domains for intercellular
signals and environmental stimuli.
well as for nucleotide sequences, found in transcription factors and other DNA- or
RNA-binding proteins.
Domains interacting with post-translational modifications (Figure 1.16) recognize

the modified amino acid together with a relatively short amino acid sequence in the
immediate neighborhood. These flanking areas may differ from protein to protein,
lending the interactions additional specificity, especially since the cognate interac-
tion domains are also variable. Thus, a protein with a distinct recognition site does
not simply interact with any other protein possessing the corresponding interaction
domain but strictly selects its partner molecule.
This selectivity of interactions is impressively demonstrated by receptor tyrosine

kinases. Upon ligand binding, these dimeric transmembrane proteins undergo
trans-autophosphorylation of several Tyr residues in their cytoplasmic domains,
thus generating contact sites for proteins with SH2 and PTB domains (see Table 1.2).
Each of those proteins has a special SH2 or PTB variant that recognizes only one of
the various phospho-Tyr residues on the receptor. In other words, each interacting
protein finds its correct place on the receptor protein (a detailed discussion of this
subject is found in Section 7.1.2). Conversely, the same recognition site may react
with several different interaction domains. For instance, SH2 domains can interact
with phospho-Tyr residues and sometimes also with SH3 domains, and PDZ do-
mains may interact with each other (homotypically) as well as with carboxy-termi-
nal amino acid sequences (see Table 1.2 and Section 7.1.4).
Figure 1.16 distinguishes between domains that interact with nonrelated do-
mains (heterotypically) and those that interact with their own type (homotypical-
ly). Examples of domains interacting exclusively in a homotypical manner are the
death domains DD and DED. They play a key role in apoptotic signaling (see Section
13.2.2). Another group of interaction domains recognizes membrane components
such as phospholipids. Such interactions enable reversible binding of proteins to
membranes and generation of signal-processing protein complexes in the neigh-
borhood of membrane receptors. Many membrane lipids are, in addition, signaling
molecules or second messengers that control the function of the interacting protein.
1.8.2 Intramolecular interactions

Interactions between regulatory domains may also occur within the same protein
molecule, with various consequences for protein function. Thus, one interaction do-
main may either suppress or promote the function of another, like an antagonist or
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DANCE ON STILTS AT THE GIRLS’ UNYAGO, NIUCHI
Newala, too, suffers from the distance of its water-supply—at least

the Newala of to-day does; there was once another Newala in a lovely
valley at the foot of the plateau. I visited it and found scarcely a trace
of houses, only a Christian cemetery, with the graves of several
missionaries and their converts, remaining as a monument of its
former glories. But the surroundings are wonderfully beautiful. A
thick grove of splendid mango-trees closes in the weather-worn
crosses and headstones; behind them, combining the useful and the
agreeable, is a whole plantation of lemon-trees covered with ripe
fruit; not the small African kind, but a much larger and also juicier
imported variety, which drops into the hands of the passing traveller,
without calling for any exertion on his part. Old Newala is now under
the jurisdiction of the native pastor, Daudi, at Chingulungulu, who,
as I am on very friendly terms with him, allows me, as a matter of
course, the use of this lemon-grove during my stay at Newala.
FEET MUTILATED BY THE RAVAGES OF THE “JIGGER”
(Sarcopsylla penetrans)
The water-supply of New Newala is in the bottom of the valley,

some 1,600 feet lower down. The way is not only long and fatiguing,
but the water, when we get it, is thoroughly bad. We are suffering not
only from this, but from the fact that the arrangements at Newala are
nothing short of luxurious. We have a separate kitchen—a hut built
against the boma palisade on the right of the baraza, the interior of
which is not visible from our usual position. Our two cooks were not
long in finding this out, and they consequently do—or rather neglect
to do—what they please. In any case they do not seem to be very
particular about the boiling of our drinking-water—at least I can
attribute to no other cause certain attacks of a dysenteric nature,
from which both Knudsen and I have suffered for some time. If a
man like Omari has to be left unwatched for a moment, he is capable
of anything. Besides this complaint, we are inconvenienced by the
state of our nails, which have become as hard as glass, and crack on
the slightest provocation, and I have the additional infliction of
pimples all over me. As if all this were not enough, we have also, for
the last week been waging war against the jigger, who has found his
Eldorado in the hot sand of the Makonde plateau. Our men are seen
all day long—whenever their chronic colds and the dysentery likewise
raging among them permit—occupied in removing this scourge of
Africa from their feet and trying to prevent the disastrous
consequences of its presence. It is quite common to see natives of
this place with one or two toes missing; many have lost all their toes,
or even the whole front part of the foot, so that a well-formed leg
ends in a shapeless stump. These ravages are caused by the female of
Sarcopsylla penetrans, which bores its way under the skin and there
develops an egg-sac the size of a pea. In all books on the subject, it is
stated that one’s attention is called to the presence of this parasite by
an intolerable itching. This agrees very well with my experience, so
far as the softer parts of the sole, the spaces between and under the
toes, and the side of the foot are concerned, but if the creature
penetrates through the harder parts of the heel or ball of the foot, it
may escape even the most careful search till it has reached maturity.
Then there is no time to be lost, if the horrible ulceration, of which
we see cases by the dozen every day, is to be prevented. It is much
easier, by the way, to discover the insect on the white skin of a
European than on that of a native, on which the dark speck scarcely
shows. The four or five jiggers which, in spite of the fact that I
constantly wore high laced boots, chose my feet to settle in, were
taken out for me by the all-accomplished Knudsen, after which I
thought it advisable to wash out the cavities with corrosive
sublimate. The natives have a different sort of disinfectant—they fill
the hole with scraped roots. In a tiny Makua village on the slope of
the plateau south of Newala, we saw an old woman who had filled all
the spaces under her toe-nails with powdered roots by way of
prophylactic treatment. What will be the result, if any, who can say?
The rest of the many trifling ills which trouble our existence are
really more comic than serious. In the absence of anything else to
smoke, Knudsen and I at last opened a box of cigars procured from
the Indian store-keeper at Lindi, and tried them, with the most
distressing results. Whether they contain opium or some other
narcotic, neither of us can say, but after the tenth puff we were both
“off,” three-quarters stupefied and unspeakably wretched. Slowly we
recovered—and what happened next? Half-an-hour later we were
once more smoking these poisonous concoctions—so insatiable is the
craving for tobacco in the tropics.
Even my present attacks of fever scarcely deserve to be taken
seriously. I have had no less than three here at Newala, all of which
have run their course in an incredibly short time. In the early
afternoon, I am busy with my old natives, asking questions and
making notes. The strong midday coffee has stimulated my spirits to
an extraordinary degree, the brain is active and vigorous, and work
progresses rapidly, while a pleasant warmth pervades the whole
body. Suddenly this gives place to a violent chill, forcing me to put on
my overcoat, though it is only half-past three and the afternoon sun
is at its hottest. Now the brain no longer works with such acuteness
and logical precision; more especially does it fail me in trying to
establish the syntax of the difficult Makua language on which I have
ventured, as if I had not enough to do without it. Under the
circumstances it seems advisable to take my temperature, and I do
so, to save trouble, without leaving my seat, and while going on with
my work. On examination, I find it to be 101·48°. My tutors are
abruptly dismissed and my bed set up in the baraza; a few minutes
later I am in it and treating myself internally with hot water and
lemon-juice.
Three hours later, the thermometer marks nearly 104°, and I make
them carry me back into the tent, bed and all, as I am now perspiring
heavily, and exposure to the cold wind just beginning to blow might
mean a fatal chill. I lie still for a little while, and then find, to my
great relief, that the temperature is not rising, but rather falling. This
is about 7.30 p.m. At 8 p.m. I find, to my unbounded astonishment,
that it has fallen below 98·6°, and I feel perfectly well. I read for an
hour or two, and could very well enjoy a smoke, if I had the
wherewithal—Indian cigars being out of the question.
Having no medical training, I am at a loss to account for this state
of things. It is impossible that these transitory attacks of high fever
should be malarial; it seems more probable that they are due to a
kind of sunstroke. On consulting my note-book, I become more and
more inclined to think this is the case, for these attacks regularly
follow extreme fatigue and long exposure to strong sunshine. They at
least have the advantage of being only short interruptions to my
work, as on the following morning I am always quite fresh and fit.
My treasure of a cook is suffering from an enormous hydrocele which
makes it difficult for him to get up, and Moritz is obliged to keep in
the dark on account of his inflamed eyes. Knudsen’s cook, a raw boy
from somewhere in the bush, knows still less of cooking than Omari;
consequently Nils Knudsen himself has been promoted to the vacant
post. Finding that we had come to the end of our supplies, he began
by sending to Chingulungulu for the four sucking-pigs which we had
bought from Matola and temporarily left in his charge; and when
they came up, neatly packed in a large crate, he callously slaughtered
the biggest of them. The first joint we were thoughtless enough to
entrust for roasting to Knudsen’s mshenzi cook, and it was
consequently uneatable; but we made the rest of the animal into a
jelly which we ate with great relish after weeks of underfeeding,
consuming incredible helpings of it at both midday and evening
meals. The only drawback is a certain want of variety in the tinned
vegetables. Dr. Jäger, to whom the Geographical Commission
entrusted the provisioning of the expeditions—mine as well as his
own—because he had more time on his hands than the rest of us,
seems to have laid in a huge stock of Teltow turnips,[46] an article of
food which is all very well for occasional use, but which quickly palls
when set before one every day; and we seem to have no other tins
left. There is no help for it—we must put up with the turnips; but I
am certain that, once I am home again, I shall not touch them for ten
years to come.
Amid all these minor evils, which, after all, go to make up the
genuine flavour of Africa, there is at least one cheering touch:
Knudsen has, with the dexterity of a skilled mechanic, repaired my 9
× 12 cm. camera, at least so far that I can use it with a little care.
How, in the absence of finger-nails, he was able to accomplish such a
ticklish piece of work, having no tool but a clumsy screw-driver for
taking to pieces and putting together again the complicated
mechanism of the instantaneous shutter, is still a mystery to me; but
he did it successfully. The loss of his finger-nails shows him in a light
contrasting curiously enough with the intelligence evinced by the
above operation; though, after all, it is scarcely surprising after his
ten years’ residence in the bush. One day, at Lindi, he had occasion
to wash a dog, which must have been in need of very thorough
cleansing, for the bottle handed to our friend for the purpose had an
extremely strong smell. Having performed his task in the most
conscientious manner, he perceived with some surprise that the dog
did not appear much the better for it, and was further surprised by
finding his own nails ulcerating away in the course of the next few
days. “How was I to know that carbolic acid has to be diluted?” he
mutters indignantly, from time to time, with a troubled gaze at his
mutilated finger-tips.
Since we came to Newala we have been making excursions in all
directions through the surrounding country, in accordance with old
habit, and also because the akida Sefu did not get together the tribal
elders from whom I wanted information so speedily as he had
promised. There is, however, no harm done, as, even if seen only
from the outside, the country and people are interesting enough.
The Makonde plateau is like a large rectangular table rounded off
at the corners. Measured from the Indian Ocean to Newala, it is
about seventy-five miles long, and between the Rovuma and the
Lukuledi it averages fifty miles in breadth, so that its superficial area
is about two-thirds of that of the kingdom of Saxony. The surface,
however, is not level, but uniformly inclined from its south-western
edge to the ocean. From the upper edge, on which Newala lies, the
eye ranges for many miles east and north-east, without encountering
any obstacle, over the Makonde bush. It is a green sea, from which
here and there thick clouds of smoke rise, to show that it, too, is
inhabited by men who carry on their tillage like so many other
primitive peoples, by cutting down and burning the bush, and
manuring with the ashes. Even in the radiant light of a tropical day
such a fire is a grand sight.
Much less effective is the impression produced just now by the
great western plain as seen from the edge of the plateau. As often as
time permits, I stroll along this edge, sometimes in one direction,
sometimes in another, in the hope of finding the air clear enough to
let me enjoy the view; but I have always been disappointed.
Wherever one looks, clouds of smoke rise from the burning bush,
and the air is full of smoke and vapour. It is a pity, for under more
favourable circumstances the panorama of the whole country up to
the distant Majeje hills must be truly magnificent. It is of little use
taking photographs now, and an outline sketch gives a very poor idea
of the scenery. In one of these excursions I went out of my way to
make a personal attempt on the Makonde bush. The present edge of
the plateau is the result of a far-reaching process of destruction
through erosion and denudation. The Makonde strata are
everywhere cut into by ravines, which, though short, are hundreds of
yards in depth. In consequence of the loose stratification of these
beds, not only are the walls of these ravines nearly vertical, but their
upper end is closed by an equally steep escarpment, so that the
western edge of the Makonde plateau is hemmed in by a series of
deep, basin-like valleys. In order to get from one side of such a ravine
to the other, I cut my way through the bush with a dozen of my men.
It was a very open part, with more grass than scrub, but even so the
short stretch of less than two hundred yards was very hard work; at
the end of it the men’s calicoes were in rags and they themselves
bleeding from hundreds of scratches, while even our strong khaki
suits had not escaped scatheless.
NATIVE PATH THROUGH THE MAKONDE BUSH, NEAR

MAHUTA
I see increasing reason to believe that the view formed some time
back as to the origin of the Makonde bush is the correct one. I have
no doubt that it is not a natural product, but the result of human
occupation. Those parts of the high country where man—as a very
slight amount of practice enables the eye to perceive at once—has not
yet penetrated with axe and hoe, are still occupied by a splendid
timber forest quite able to sustain a comparison with our mixed
forests in Germany. But wherever man has once built his hut or tilled
his field, this horrible bush springs up. Every phase of this process
may be seen in the course of a couple of hours’ walk along the main
road. From the bush to right or left, one hears the sound of the axe—
not from one spot only, but from several directions at once. A few
steps further on, we can see what is taking place. The brush has been
cut down and piled up in heaps to the height of a yard or more,
between which the trunks of the large trees stand up like the last
pillars of a magnificent ruined building. These, too, present a
melancholy spectacle: the destructive Makonde have ringed them—
cut a broad strip of bark all round to ensure their dying off—and also
piled up pyramids of brush round them. Father and son, mother and
son-in-law, are chopping away perseveringly in the background—too
busy, almost, to look round at the white stranger, who usually excites
so much interest. If you pass by the same place a week later, the piles
of brushwood have disappeared and a thick layer of ashes has taken
the place of the green forest. The large trees stretch their
smouldering trunks and branches in dumb accusation to heaven—if
they have not already fallen and been more or less reduced to ashes,
perhaps only showing as a white stripe on the dark ground.
This work of destruction is carried out by the Makonde alike on the
virgin forest and on the bush which has sprung up on sites already
cultivated and deserted. In the second case they are saved the trouble
of burning the large trees, these being entirely absent in the
secondary bush.
After burning this piece of forest ground and loosening it with the
hoe, the native sows his corn and plants his vegetables. All over the
country, he goes in for bed-culture, which requires, and, in fact,
receives, the most careful attention. Weeds are nowhere tolerated in
the south of German East Africa. The crops may fail on the plains,
where droughts are frequent, but never on the plateau with its
abundant rains and heavy dews. Its fortunate inhabitants even have
the satisfaction of seeing the proud Wayao and Wamakua working
for them as labourers, driven by hunger to serve where they were
accustomed to rule.
But the light, sandy soil is soon exhausted, and would yield no
harvest the second year if cultivated twice running. This fact has
been familiar to the native for ages; consequently he provides in
time, and, while his crop is growing, prepares the next plot with axe
and firebrand. Next year he plants this with his various crops and
lets the first piece lie fallow. For a short time it remains waste and
desolate; then nature steps in to repair the destruction wrought by
man; a thousand new growths spring out of the exhausted soil, and
even the old stumps put forth fresh shoots. Next year the new growth
is up to one’s knees, and in a few years more it is that terrible,
impenetrable bush, which maintains its position till the black
occupier of the land has made the round of all the available sites and
come back to his starting point.
The Makonde are, body and soul, so to speak, one with this bush.
According to my Yao informants, indeed, their name means nothing
else but “bush people.” Their own tradition says that they have been
settled up here for a very long time, but to my surprise they laid great
stress on an original immigration. Their old homes were in the
south-east, near Mikindani and the mouth of the Rovuma, whence
their peaceful forefathers were driven by the continual raids of the
Sakalavas from Madagascar and the warlike Shirazis[47] of the coast,
to take refuge on the almost inaccessible plateau. I have studied
African ethnology for twenty years, but the fact that changes of
population in this apparently quiet and peaceable corner of the earth
could have been occasioned by outside enterprises taking place on
the high seas, was completely new to me. It is, no doubt, however,
correct.
The charming tribal legend of the Makonde—besides informing us
of other interesting matters—explains why they have to live in the
thickest of the bush and a long way from the edge of the plateau,
instead of making their permanent homes beside the purling brooks
and springs of the low country.
“The place where the tribe originated is Mahuta, on the southern
side of the plateau towards the Rovuma, where of old time there was
nothing but thick bush. Out of this bush came a man who never
washed himself or shaved his head, and who ate and drank but little.
He went out and made a human figure from the wood of a tree
growing in the open country, which he took home to his abode in the
bush and there set it upright. In the night this image came to life and
was a woman. The man and woman went down together to the
Rovuma to wash themselves. Here the woman gave birth to a still-
born child. They left that place and passed over the high land into the
valley of the Mbemkuru, where the woman had another child, which
was also born dead. Then they returned to the high bush country of
Mahuta, where the third child was born, which lived and grew up. In
course of time, the couple had many more children, and called
themselves Wamatanda. These were the ancestral stock of the
Makonde, also called Wamakonde,[48] i.e., aborigines. Their
forefather, the man from the bush, gave his children the command to
bury their dead upright, in memory of the mother of their race who
was cut out of wood and awoke to life when standing upright. He also
warned them against settling in the valleys and near large streams,
for sickness and death dwelt there. They were to make it a rule to
have their huts at least an hour’s walk from the nearest watering-
place; then their children would thrive and escape illness.”
The explanation of the name Makonde given by my informants is
somewhat different from that contained in the above legend, which I
extract from a little book (small, but packed with information), by
Pater Adams, entitled Lindi und sein Hinterland. Otherwise, my
results agree exactly with the statements of the legend. Washing?
Hapana—there is no such thing. Why should they do so? As it is, the
supply of water scarcely suffices for cooking and drinking; other
people do not wash, so why should the Makonde distinguish himself
by such needless eccentricity? As for shaving the head, the short,
woolly crop scarcely needs it,[49] so the second ancestral precept is
likewise easy enough to follow. Beyond this, however, there is
nothing ridiculous in the ancestor’s advice. I have obtained from
various local artists a fairly large number of figures carved in wood,
ranging from fifteen to twenty-three inches in height, and
representing women belonging to the great group of the Mavia,
Makonde, and Matambwe tribes. The carving is remarkably well
done and renders the female type with great accuracy, especially the
keloid ornamentation, to be described later on. As to the object and
meaning of their works the sculptors either could or (more probably)
would tell me nothing, and I was forced to content myself with the
scanty information vouchsafed by one man, who said that the figures
were merely intended to represent the nembo—the artificial
deformations of pelele, ear-discs, and keloids. The legend recorded
by Pater Adams places these figures in a new light. They must surely
be more than mere dolls; and we may even venture to assume that
they are—though the majority of present-day Makonde are probably
unaware of the fact—representations of the tribal ancestress.
The references in the legend to the descent from Mahuta to the
Rovuma, and to a journey across the highlands into the Mbekuru
valley, undoubtedly indicate the previous history of the tribe, the
travels of the ancestral pair typifying the migrations of their
descendants. The descent to the neighbouring Rovuma valley, with
its extraordinary fertility and great abundance of game, is intelligible
at a glance—but the crossing of the Lukuledi depression, the ascent
to the Rondo Plateau and the descent to the Mbemkuru, also lie
within the bounds of probability, for all these districts have exactly
the same character as the extreme south. Now, however, comes a
point of especial interest for our bacteriological age. The primitive
Makonde did not enjoy their lives in the marshy river-valleys.
Disease raged among them, and many died. It was only after they
had returned to their original home near Mahuta, that the health
conditions of these people improved. We are very apt to think of the
African as a stupid person whose ignorance of nature is only equalled
by his fear of it, and who looks on all mishaps as caused by evil
spirits and malignant natural powers. It is much more correct to
assume in this case that the people very early learnt to distinguish
districts infested with malaria from those where it is absent.
This knowledge is crystallized in the
ancestral warning against settling in the
valleys and near the great waters, the
dwelling-places of disease and death. At the
same time, for security against the hostile
Mavia south of the Rovuma, it was enacted
that every settlement must be not less than a
certain distance from the southern edge of the
plateau. Such in fact is their mode of life at the
present day. It is not such a bad one, and
certainly they are both safer and more
comfortable than the Makua, the recent
intruders from the south, who have made USUAL METHOD OF
good their footing on the western edge of the CLOSING HUT-DOOR
plateau, extending over a fairly wide belt of
country. Neither Makua nor Makonde show in their dwellings
anything of the size and comeliness of the Yao houses in the plain,
especially at Masasi, Chingulungulu and Zuza’s. Jumbe Chauro, a
Makonde hamlet not far from Newala, on the road to Mahuta, is the
most important settlement of the tribe I have yet seen, and has fairly
spacious huts. But how slovenly is their construction compared with
the palatial residences of the elephant-hunters living in the plain.
The roofs are still more untidy than in the general run of huts during
the dry season, the walls show here and there the scanty beginnings
or the lamentable remains of the mud plastering, and the interior is a
veritable dog-kennel; dirt, dust and disorder everywhere. A few huts
only show any attempt at division into rooms, and this consists
merely of very roughly-made bamboo partitions. In one point alone
have I noticed any indication of progress—in the method of fastening
the door. Houses all over the south are secured in a simple but
ingenious manner. The door consists of a set of stout pieces of wood
or bamboo, tied with bark-string to two cross-pieces, and moving in
two grooves round one of the door-posts, so as to open inwards. If
the owner wishes to leave home, he takes two logs as thick as a man’s
upper arm and about a yard long. One of these is placed obliquely
against the middle of the door from the inside, so as to form an angle
of from 60° to 75° with the ground. He then places the second piece
horizontally across the first, pressing it downward with all his might.
It is kept in place by two strong posts planted in the ground a few
inches inside the door. This fastening is absolutely safe, but of course
cannot be applied to both doors at once, otherwise how could the
owner leave or enter his house? I have not yet succeeded in finding
out how the back door is fastened.
MAKONDE LOCK AND KEY AT JUMBE CHAURO

This is the general way of closing a house. The Makonde at Jumbe
Chauro, however, have a much more complicated, solid and original
one. Here, too, the door is as already described, except that there is
only one post on the inside, standing by itself about six inches from
one side of the doorway. Opposite this post is a hole in the wall just
large enough to admit a man’s arm. The door is closed inside by a
large wooden bolt passing through a hole in this post and pressing
with its free end against the door. The other end has three holes into
which fit three pegs running in vertical grooves inside the post. The
door is opened with a wooden key about a foot long, somewhat
curved and sloped off at the butt; the other end has three pegs
corresponding to the holes, in the bolt, so that, when it is thrust
through the hole in the wall and inserted into the rectangular
opening in the post, the pegs can be lifted and the bolt drawn out.[50]
MODE OF INSERTING THE KEY
With no small pride first one householder and then a second

showed me on the spot the action of this greatest invention of the
Makonde Highlands. To both with an admiring exclamation of
“Vizuri sana!” (“Very fine!”). I expressed the wish to take back these
marvels with me to Ulaya, to show the Wazungu what clever fellows
the Makonde are. Scarcely five minutes after my return to camp at
Newala, the two men came up sweating under the weight of two
heavy logs which they laid down at my feet, handing over at the same
time the keys of the fallen fortress. Arguing, logically enough, that if
the key was wanted, the lock would be wanted with it, they had taken
their axes and chopped down the posts—as it never occurred to them
to dig them out of the ground and so bring them intact. Thus I have
two badly damaged specimens, and the owners, instead of praise,
come in for a blowing-up.
The Makua huts in the environs of Newala are especially
miserable; their more than slovenly construction reminds one of the
temporary erections of the Makua at Hatia’s, though the people here
have not been concerned in a war. It must therefore be due to
congenital idleness, or else to the absence of a powerful chief. Even
the baraza at Mlipa’s, a short hour’s walk south-east of Newala,
shares in this general neglect. While public buildings in this country
are usually looked after more or less carefully, this is in evident
danger of being blown over by the first strong easterly gale. The only
attractive object in this whole district is the grave of the late chief
Mlipa. I visited it in the morning, while the sun was still trying with
partial success to break through the rolling mists, and the circular
grove of tall euphorbias, which, with a broken pot, is all that marks
the old king’s resting-place, impressed one with a touch of pathos.
Even my very materially-minded carriers seemed to feel something
of the sort, for instead of their usual ribald songs, they chanted
solemnly, as we marched on through the dense green of the Makonde
bush:—
“We shall arrive with the great master; we stand in a row and have
no fear about getting our food and our money from the Serkali (the
Government). We are not afraid; we are going along with the great
master, the lion; we are going down to the coast and back.”
With regard to the characteristic features of the various tribes here
on the western edge of the plateau, I can arrive at no other
conclusion than the one already come to in the plain, viz., that it is
impossible for anyone but a trained anthropologist to assign any
given individual at once to his proper tribe. In fact, I think that even
an anthropological specialist, after the most careful examination,
might find it a difficult task to decide. The whole congeries of peoples
collected in the region bounded on the west by the great Central
African rift, Tanganyika and Nyasa, and on the east by the Indian
Ocean, are closely related to each other—some of their languages are
only distinguished from one another as dialects of the same speech,
and no doubt all the tribes present the same shape of skull and
structure of skeleton. Thus, surely, there can be no very striking
differences in outward appearance.
Even did such exist, I should have no time
to concern myself with them, for day after day,
I have to see or hear, as the case may be—in
any case to grasp and record—an
extraordinary number of ethnographic
phenomena. I am almost disposed to think it
fortunate that some departments of inquiry, at
least, are barred by external circumstances.
Chief among these is the subject of iron-
working. We are apt to think of Africa as a
country where iron ore is everywhere, so to
speak, to be picked up by the roadside, and
where it would be quite surprising if the
inhabitants had not learnt to smelt the
material ready to their hand. In fact, the
knowledge of this art ranges all over the
continent, from the Kabyles in the north to the
Kafirs in the south. Here between the Rovuma
and the Lukuledi the conditions are not so
favourable. According to the statements of the
Makonde, neither ironstone nor any other
form of iron ore is known to them. They have
not therefore advanced to the art of smelting
the metal, but have hitherto bought all their
THE ANCESTRESS OF
THE MAKONDE
iron implements from neighbouring tribes.
Even in the plain the inhabitants are not much
better off. Only one man now living is said to
understand the art of smelting iron. This old fundi lives close to
Huwe, that isolated, steep-sided block of granite which rises out of
the green solitude between Masasi and Chingulungulu, and whose
jagged and splintered top meets the traveller’s eye everywhere. While
still at Masasi I wished to see this man at work, but was told that,
frightened by the rising, he had retired across the Rovuma, though
he would soon return. All subsequent inquiries as to whether the
fundi had come back met with the genuine African answer, “Bado”
(“Not yet”).
BRAZIER
Some consolation was afforded me by a brassfounder, whom I

came across in the bush near Akundonde’s. This man is the favourite
of women, and therefore no doubt of the gods; he welds the glittering
brass rods purchased at the coast into those massive, heavy rings
which, on the wrists and ankles of the local fair ones, continually give
me fresh food for admiration. Like every decent master-craftsman he
had all his tools with him, consisting of a pair of bellows, three
crucibles and a hammer—nothing more, apparently. He was quite
willing to show his skill, and in a twinkling had fixed his bellows on
the ground. They are simply two goat-skins, taken off whole, the four
legs being closed by knots, while the upper opening, intended to
admit the air, is kept stretched by two pieces of wood. At the lower
end of the skin a smaller opening is left into which a wooden tube is
stuck. The fundi has quickly borrowed a heap of wood-embers from
the nearest hut; he then fixes the free ends of the two tubes into an
earthen pipe, and clamps them to the ground by means of a bent
piece of wood. Now he fills one of his small clay crucibles, the dross
on which shows that they have been long in use, with the yellow
material, places it in the midst of the embers, which, at present are
only faintly glimmering, and begins his work. In quick alternation
the smith’s two hands move up and down with the open ends of the
bellows; as he raises his hand he holds the slit wide open, so as to let
the air enter the skin bag unhindered. In pressing it down he closes
the bag, and the air puffs through the bamboo tube and clay pipe into
the fire, which quickly burns up. The smith, however, does not keep
on with this work, but beckons to another man, who relieves him at
the bellows, while he takes some more tools out of a large skin pouch
carried on his back. I look on in wonder as, with a smooth round
stick about the thickness of a finger, he bores a few vertical holes into
the clean sand of the soil. This should not be difficult, yet the man
seems to be taking great pains over it. Then he fastens down to the
ground, with a couple of wooden clamps, a neat little trough made by
splitting a joint of bamboo in half, so that the ends are closed by the
two knots. At last the yellow metal has attained the right consistency,
and the fundi lifts the crucible from the fire by means of two sticks
split at the end to serve as tongs. A short swift turn to the left—a
tilting of the crucible—and the molten brass, hissing and giving forth
clouds of smoke, flows first into the bamboo mould and then into the
holes in the ground.
The technique of this backwoods craftsman may not be very far
advanced, but it cannot be denied that he knows how to obtain an
adequate result by the simplest means. The ladies of highest rank in
this country—that is to say, those who can afford it, wear two kinds
of these massive brass rings, one cylindrical, the other semicircular
in section. The latter are cast in the most ingenious way in the
bamboo mould, the former in the circular hole in the sand. It is quite
a simple matter for the fundi to fit these bars to the limbs of his fair
customers; with a few light strokes of his hammer he bends the
pliable brass round arm or ankle without further inconvenience to
the wearer.
SHAPING THE POT
SMOOTHING WITH MAIZE-COB
CUTTING THE EDGE

FINISHING THE BOTTOM
LAST SMOOTHING BEFORE

BURNING
FIRING THE BRUSH-PILE

LIGHTING THE FARTHER SIDE OF
THE PILE
TURNING THE RED-HOT VESSEL
NYASA WOMAN MAKING POTS AT MASASI

Pottery is an art which must always and everywhere excite the
interest of the student, just because it is so intimately connected with
the development of human culture, and because its relics are one of
the principal factors in the reconstruction of our own condition in
prehistoric times. I shall always remember with pleasure the two or
three afternoons at Masasi when Salim Matola’s mother, a slightly-
built, graceful, pleasant-looking woman, explained to me with
touching patience, by means of concrete illustrations, the ceramic art
of her people. The only implements for this primitive process were a
lump of clay in her left hand, and in the right a calabash containing
the following valuables: the fragment of a maize-cob stripped of all
its grains, a smooth, oval pebble, about the size of a pigeon’s egg, a
few chips of gourd-shell, a bamboo splinter about the length of one’s
hand, a small shell, and a bunch of some herb resembling spinach.
Nothing more. The woman scraped with the
shell a round, shallow hole in the soft, fine
sand of the soil, and, when an active young
girl had filled the calabash with water for her,
she began to knead the clay. As if by magic it
gradually assumed the shape of a rough but
already well-shaped vessel, which only wanted
a little touching up with the instruments
before mentioned. I looked out with the
MAKUA WOMAN closest attention for any indication of the use
MAKING A POT. of the potter’s wheel, in however rudimentary
SHOWS THE a form, but no—hapana (there is none). The
BEGINNINGS OF THE embryo pot stood firmly in its little
POTTER’S WHEEL
depression, and the woman walked round it in
a stooping posture, whether she was removing
small stones or similar foreign bodies with the maize-cob, smoothing
the inner or outer surface with the splinter of bamboo, or later, after
letting it dry for a day, pricking in the ornamentation with a pointed
bit of gourd-shell, or working out the bottom, or cutting the edge
with a sharp bamboo knife, or giving the last touches to the finished
vessel. This occupation of the women is infinitely toilsome, but it is
without doubt an accurate reproduction of the process in use among
our ancestors of the Neolithic and Bronze ages.
There is no doubt that the invention of pottery, an item in human
progress whose importance cannot be over-estimated, is due to
women. Rough, coarse and unfeeling, the men of the horde range
over the countryside. When the united cunning of the hunters has
succeeded in killing the game; not one of them thinks of carrying
home the spoil. A bright fire, kindled by a vigorous wielding of the
drill, is crackling beside them; the animal has been cleaned and cut
up secundum artem, and, after a slight singeing, will soon disappear
under their sharp teeth; no one all this time giving a single thought
to wife or child.
To what shifts, on the other hand, the primitive wife, and still more
the primitive mother, was put! Not even prehistoric stomachs could
endure an unvarying diet of raw food. Something or other suggested
the beneficial effect of hot water on the majority of approved but
indigestible dishes. Perhaps a neighbour had tried holding the hard
roots or tubers over the fire in a calabash filled with water—or maybe
an ostrich-egg-shell, or a hastily improvised vessel of bark. They
became much softer and more palatable than they had previously
been; but, unfortunately, the vessel could not stand the fire and got
charred on the outside. That can be remedied, thought our
ancestress, and plastered a layer of wet clay round a similar vessel.
This is an improvement; the cooking utensil remains uninjured, but
the heat of the fire has shrunk it, so that it is loose in its shell. The
next step is to detach it, so, with a firm grip and a jerk, shell and
kernel are separated, and pottery is invented. Perhaps, however, the
discovery which led to an intelligent use of the burnt-clay shell, was
made in a slightly different way. Ostrich-eggs and calabashes are not
to be found in every part of the world, but everywhere mankind has
arrived at the art of making baskets out of pliant materials, such as
bark, bast, strips of palm-leaf, supple twigs, etc. Our inventor has no
water-tight vessel provided by nature. “Never mind, let us line the
basket with clay.” This answers the purpose, but alas! the basket gets
burnt over the blazing fire, the woman watches the process of
cooking with increasing uneasiness, fearing a leak, but no leak
appears. The food, done to a turn, is eaten with peculiar relish; and
the cooking-vessel is examined, half in curiosity, half in satisfaction
at the result. The plastic clay is now hard as stone, and at the same
time looks exceedingly well, for the neat plaiting of the burnt basket
is traced all over it in a pretty pattern. Thus, simultaneously with
pottery, its ornamentation was invented.
Primitive woman has another claim to respect. It was the man,
roving abroad, who invented the art of producing fire at will, but the
woman, unable to imitate him in this, has been a Vestal from the
earliest times. Nothing gives so much trouble as the keeping alight of
the smouldering brand, and, above all, when all the men are absent
from the camp. Heavy rain-clouds gather, already the first large
drops are falling, the first gusts of the storm rage over the plain. The
little flame, a greater anxiety to the woman than her own children,
flickers unsteadily in the blast. What is to be done? A sudden thought
occurs to her, and in an instant she has constructed a primitive hut
out of strips of bark, to protect the flame against rain and wind.
This, or something very like it, was the way in which the principle
of the house was discovered; and even the most hardened misogynist
cannot fairly refuse a woman the credit of it. The protection of the
hearth-fire from the weather is the germ from which the human
dwelling was evolved. Men had little, if any share, in this forward
step, and that only at a late stage. Even at the present day, the
plastering of the housewall with clay and the manufacture of pottery
are exclusively the women’s business. These are two very significant
survivals. Our European kitchen-garden, too, is originally a woman’s
invention, and the hoe, the primitive instrument of agriculture, is,
characteristically enough, still used in this department. But the
noblest achievement which we owe to the other sex is unquestionably
the art of cookery. Roasting alone—the oldest process—is one for
which men took the hint (a very obvious one) from nature. It must
have been suggested by the scorched carcase of some animal
overtaken by the destructive forest-fires. But boiling—the process of
improving organic substances by the help of water heated to boiling-
point—is a much later discovery. It is so recent that it has not even
yet penetrated to all parts of the world. The Polynesians understand
how to steam food, that is, to cook it, neatly wrapped in leaves, in a
hole in the earth between hot stones, the air being excluded, and
(sometimes) a few drops of water sprinkled on the stones; but they
do not understand boiling.
To come back from this digression, we find that the slender Nyasa
woman has, after once more carefully examining the finished pot,
put it aside in the shade to dry. On the following day she sends me
word by her son, Salim Matola, who is always on hand, that she is
going to do the burning, and, on coming out of my house, I find her
already hard at work. She has spread on the ground a layer of very
dry sticks, about as thick as one’s thumb, has laid the pot (now of a
yellowish-grey colour) on them, and is piling brushwood round it.
My faithful Pesa mbili, the mnyampara, who has been standing by,
most obligingly, with a lighted stick, now hands it to her. Both of
them, blowing steadily, light the pile on the lee side, and, when the
flame begins to catch, on the weather side also. Soon the whole is in a
blaze, but the dry fuel is quickly consumed and the fire dies down, so
that we see the red-hot vessel rising from the ashes. The woman
turns it continually with a long stick, sometimes one way and
sometimes another, so that it may be evenly heated all over. In
twenty minutes she rolls it out of the ash-heap, takes up the bundle
of spinach, which has been lying for two days in a jar of water, and
sprinkles the red-hot clay with it. The places where the drops fall are
marked by black spots on the uniform reddish-brown surface. With a
sigh of relief, and with visible satisfaction, the woman rises to an
erect position; she is standing just in a line between me and the fire,
from which a cloud of smoke is just rising: I press the ball of my
camera, the shutter clicks—the apotheosis is achieved! Like a
priestess, representative of her inventive sex, the graceful woman
stands: at her feet the hearth-fire she has given us beside her the
invention she has devised for us, in the background the home she has
built for us.
At Newala, also, I have had the manufacture of pottery carried on
in my presence. Technically the process is better than that already
described, for here we find the beginnings of the potter’s wheel,
which does not seem to exist in the plains; at least I have seen
nothing of the sort. The artist, a frightfully stupid Makua woman, did
not make a depression in the ground to receive the pot she was about
to shape, but used instead a large potsherd. Otherwise, she went to
work in much the same way as Salim’s mother, except that she saved
herself the trouble of walking round and round her work by squatting
at her ease and letting the pot and potsherd rotate round her; this is
surely the first step towards a machine. But it does not follow that
the pot was improved by the process. It is true that it was beautifully
rounded and presented a very creditable appearance when finished,
but the numerous large and small vessels which I have seen, and, in
part, collected, in the “less advanced” districts, are no less so. We
moderns imagine that instruments of precision are necessary to
produce excellent results. Go to the prehistoric collections of our
museums and look at the pots, urns and bowls of our ancestors in the
dim ages of the past, and you will at once perceive your error.
MAKING LONGITUDINAL CUT IN
BARK
DRAWING THE BARK OFF THE LOG
REMOVING THE OUTER BARK

BEATING THE BARK
WORKING THE BARK-CLOTH AFTER BEATING, TO MAKE IT

SOFT
MANUFACTURE OF BARK-CLOTH AT NEWALA

To-day, nearly the whole population of German East Africa is
clothed in imported calico. This was not always the case; even now in
some parts of the north dressed skins are still the prevailing wear,
and in the north-western districts—east and north of Lake
Tanganyika—lies a zone where bark-cloth has not yet been
superseded. Probably not many generations have passed since such
bark fabrics and kilts of skins were the only clothing even in the
south. Even to-day, large quantities of this bright-red or drab
material are still to be found; but if we wish to see it, we must look in
the granaries and on the drying stages inside the native huts, where
it serves less ambitious uses as wrappings for those seeds and fruits
which require to be packed with special care. The salt produced at
Masasi, too, is packed for transport to a distance in large sheets of
bark-cloth. Wherever I found it in any degree possible, I studied the
process of making this cloth. The native requisitioned for the
purpose arrived, carrying a log between two and three yards long and
as thick as his thigh, and nothing else except a curiously-shaped
mallet and the usual long, sharp and pointed knife which all men and
boys wear in a belt at their backs without a sheath—horribile dictu!
[51]
Silently he squats down before me, and with two rapid cuts has
drawn a couple of circles round the log some two yards apart, and
slits the bark lengthwise between them with the point of his knife.
With evident care, he then scrapes off the outer rind all round the
log, so that in a quarter of an hour the inner red layer of the bark
shows up brightly-coloured between the two untouched ends. With
some trouble and much caution, he now loosens the bark at one end,
and opens the cylinder. He then stands up, takes hold of the free
edge with both hands, and turning it inside out, slowly but steadily
pulls it off in one piece. Now comes the troublesome work of
scraping all superfluous particles of outer bark from the outside of
the long, narrow piece of material, while the inner side is carefully
scrutinised for defective spots. At last it is ready for beating. Having
signalled to a friend, who immediately places a bowl of water beside
him, the artificer damps his sheet of bark all over, seizes his mallet,
lays one end of the stuff on the smoothest spot of the log, and
hammers away slowly but continuously. “Very simple!” I think to
myself. “Why, I could do that, too!”—but I am forced to change my
opinions a little later on; for the beating is quite an art, if the fabric is
not to be beaten to pieces. To prevent the breaking of the fibres, the
stuff is several times folded across, so as to interpose several
thicknesses between the mallet and the block. At last the required
state is reached, and the fundi seizes the sheet, still folded, by both
ends, and wrings it out, or calls an assistant to take one end while he
holds the other. The cloth produced in this way is not nearly so fine
and uniform in texture as the famous Uganda bark-cloth, but it is
quite soft, and, above all, cheap.
Now, too, I examine the mallet. My craftsman has been using the
simpler but better form of this implement, a conical block of some
hard wood, its base—the striking surface—being scored across and
across with more or less deeply-cut grooves, and the handle stuck
into a hole in the middle. The other and earlier form of mallet is
shaped in the same way, but the head is fastened by an ingenious
network of bark strips into the split bamboo serving as a handle. The
observation so often made, that ancient customs persist longest in
connection with religious ceremonies and in the life of children, here
finds confirmation. As we shall soon see, bark-cloth is still worn
during the unyago,[52] having been prepared with special solemn
ceremonies; and many a mother, if she has no other garment handy,
will still put her little one into a kilt of bark-cloth, which, after all,
looks better, besides being more in keeping with its African
surroundings, than the ridiculous bit of print from Ulaya.
MAKUA WOMEN

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Cellular Signal Processing: An

Introduction to the Molecular

All Life is problem solving

ATP hydrolysis, protein phosphorylation, and discharge of the membrane potential.

Instructor Resources Website

Accessible from www.garlandscience.com, the Instructor’s Resource Site requires

Chapter 1 The “Brain of the Cell”: Data Processing by Protein Networks 1

Chapter 2 Supplying the Network with Energy: Basic Biochemistry of

Chapter 3 Evolution of Cellular Data Processing 87

Chapter 4 Basic Equipment: G-Proteins, Second Messengers, and

Chapter 5 Signal Transduction by Receptors with Seven

Chapter 6 Signal Transduction by Serine/Threonine Kinase-Coupled

Chapter 7 Signal Transduction by Tyrosine Kinase- and Protein

Chapter 8 Eukaryotic Gene Transcription: The Ultimate Target of

Chapter 9 Signals Controlling mRNA Translation 329

Chapter 10 Signal Transduction by Small G-Proteins: The Art of

Chapter 11 Mitogen-activated Protein Kinase and Nuclear Factor κB

Chapter 12 Regulation of Cell Division 423

Chapter 13 Signal Transduction by Proteolysis, and Programmed

Chapter 14 Signal Transduction by Ions 485

Chapter 15 Sensory Signal Processing 543

Chapter 16 Signaling at Synapses: Neurotransmitters and their

Chapter 17 Putting Together the Pieces: The Approach of Systems

Chapter 1 The “Brain of the Cell”: 3.3 Signal-controlled membrane transport:

Chapter 14 Signal Transduction 16.3 γ-Aminobutyric acid and glycine receptors

16.1 Neurons and synapses 563 Index 623

In this chapter we shall address the following questions:

1.1 Metaphors and reductionism: temptations

SOCIETY network of individuals

and molecular biology (including genome- and proteome-wide screening studies),

Nevertheless, certain basic principles and a couple of biochemical reactions upon

1.2 Information and signals

In other words, the network of enzyme-catalyzed metabolic reactions, as well as the

Information is understood as the content of news exchanged between partners—let

In information technology, signals are mostly electromagnetic impulses and waves,

Table 1.1 Biological signals

Environmental stimuli: sound, light, temperature, touch, taste, and smell;

Between organisms: pheromones, gamones, sound, sight, touch, taste, smell

Between cells: systemic mediators such as hormones; local mediators such as

Within cells: second messengers such as cyclic nucleotides, diacylglycerol,

Within protein molecules: conformational changes

picture is based on both amplitude- and frequency-modulated light signals. An anal-

From the principle of medium-independent signaling it follows that signals resem-

Figure 1.3 Signals are ambiguous

uterus proliferation, differentiation

1.3 Proteins are binary switches

Let us assume S to be a stimulatory signal or, in pharmacological terms, an agonist.

binding of additional signaling molecules, resulting in conformational changes of output

1.4 Signal-transducing proteins are “nanoneurons”

Since function strictly depends on the three-dimensional structure of a protein, the

1.5 Proteins form logical gates and “neural networks”

1.6 Privacy versus publicity

Figure 1.11 Private versus public

Another hallmark of biological signaling is temporal transitoriness. A neuronal

1.7 Cross talking and network formation

Impressive microscopic photographs and three-dimensional models showing the

1.7.1 Network biology

Figure 1.13 Diffuse signal

Figure 1.14 The cytoskeleton:

P13K1a ASAP1 p190RhoGAP Cas Paxillin gamma PLC SHC

1.7.2 Some remarks on the complexity of the “cellular brain”

Each of these proteins is expected to undergo covalent post-translational mod-

1.8 Interaction domains: how the network is plugged

16.1 Neurons and synapses 563 Index 623