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The Cover
The cover image shows the formation of an autophagosome, in which organ-
elles and cytosol are engulfed in cytoplasmic membranes. Original painting
by David S. Goodsell, based on the scientific design of Daniel J. Klionsky.

The Artist
David S. Goodsell is an Associate Professor of Molecular Biology at the
Scripps Research Institute. His illustrated books, The Machinery of Life and
Our Molecular Nature, explore biological molecules and their diverse roles
within living cells, and his new book, Bionanotechnology: Lessons from Nature,
presents the growing connections between biology and nanotechnology.
More information may be found at: http://mgl.scripps.edu/people/goodsell

The Cell: A Molecular Approach, Seventh Edition

Copyright 2016 by Geoffrey M. Cooper. All rights reserved.
This book may not be reproduced in whole or in part without permission.

Address orders and requests for examination copies to: Sinauer Associates
P.O. Box 407, 23 Plumtree Road, Sunderland, MA 01375 U.S.A.
Phone: 413-549-4300
FAX: 413-549-1118
email: orders@sinauer.com
www.sinauer.com

Library of Congress Cataloging-in-Publication Data

Cooper, Geoffrey M., author.

The cell : a molecular approach / Geoffrey M. Cooper, Robert E. Hausman.
-- Seventh edition.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-60535-290-9
I. Hausman, Robert E., 1947-2015, author. II. Title.
[DNLM: 1. Cells. 2. Cell Biology. 3. Cell Physiological Phenomena.
4. Molecular Biology. QU 300]
QH581.2
571.6--dc23
2015032684
Printed in U.S.A
6 5 4 3 2 1
To my friend, colleague, and coauthor,
Robert E. Hausman
(1947–2015)

Geoffrey M. Cooper
Brief Table of Contents
PART I
Fundamentals and Foundations 1
Chapter 1 An Overview of Cells and Cell Research 3
Chapter 2 Molecules and Membranes 47
Chapter 3 Bioenergetics and Metabolism 81
Chapter 4 Fundamentals of Molecular Biology 111
Chapter 5 Genomics, Proteomics, and Systems Biology 157

PART II
The Flow of Genetic Information 185
Chapter 6 Genes and Genomes 187
Chapter 7 Replication, Maintenance, and Rearrangements
of Genomic DNA 217
Chapter 8 RNA Synthesis and Processing 259
Chapter 9 Protein Synthesis, Processing, and Regulation 317

PART III
Cell Structure and Function 365
Chapter 10 The Nucleus 367
Chapter 11 Protein Sorting and Transport 397
Chapter 12 Mitochondria, Chloroplasts, and Peroxisomes 447
Chapter 13 The Cytoskeleton and Cell Movement 479
Chapter 14 The Plasma Membrane 531
Chapter 15 Cell Walls, the Extracellular Matrix, and Cell Interactions 571

PART IV
Cell Regulation 599
Chapter 16 Cell Signaling 601
Chapter 17 The Cell Cycle 651
Chapter 18 Cell Death and Cell Renewal 691
Chapter 19 Cancer 723
Contents
PART I
Fundamentals and Foundations 1
Chapter 1 An Overview of Cells and Cell Research 3
The Origin and Evolution of Cells 4 Tools of Cell Biology 23
The first cell 4 Light microscopy 23
The evolution of metabolism 7 Electron microscopy 30
Present-day prokaryotes 8 Super-resolution light microscopy 32
Eukaryotic cells 9 Subcellular fractionation 34
The origin of eukaryotes 11 Growth of animal cells in culture 37
The development of multicellular organisms 13 Key Experiment
HeLa Cells 39
Cells as Experimental Models 17 Culture of plant cells 39
E. coli 17
Viruses 40
Yeasts 18
Molecular Medicine
Caenorhabditis elegans 19 Viruses and Cancer 41
Drosophila melanogaster 20 SUMMARY AND KEY TERMS 43
Arabidopsis thaliana 20 QUESTIONS 44
Vertebrates 20 REFERENCES AND FURTHER READING 45

Chapter 2 Molecules and Membranes 47

The Molecules of Cells 47 The catalytic activity of enzymes 62
Carbohydrates 48 Mechanisms of enzymatic catalysis 63
Lipids 50 Coenzymes 66
Nucleic acids 54 Regulation of enzyme activity 68
Proteins 56 Cell Membranes 70
Key Experiment Membrane lipids 70
The Folding of Polypeptide Chains 58
Membrane proteins 71
Enzymes as Biological Catalysts 62 Key Experiment
The Structure of Cell Membranes 73
viii Contents

Transport across cell membranes 74 QUESTIONS 78

SUMMARY AND KEY TERMS 77 REFERENCES AND FURTHER READING 78

Chapter 3 Bioenergetics and Metabolism 81

Metabolic Energy and ATP 81 ATP synthesis 98
Free energy and ATP 81 Synthesis of glucose 99
Glycolysis and the Krebs cycle 84 The Biosynthesis of Cell Constituents 101
The derivation of energy from lipids 89 Carbohydrates 101
Electron Transport and Oxidative Lipids 102
Phosphorylation 89 Proteins 103
The electron transport chain 90 Key Experiment
Antimetabolites and Chemotherapy 105
Chemiosmotic coupling 92
Key Experiment Nucleic acids 106
The Chemiosmotic Theory 93 SUMMARY AND KEY TERMS 107
QUESTIONS 108
Photosynthesis 95
REFERENCES AND FURTHER READING 109
Electron transport 96

Chapter 4 Fundamentals of Molecular Biology 111

Heredity, Genes, and DNA 111
Genes and chromosomes 111
Genes and enzymes 115
Identification of DNA as the genetic material 115
The structure of DNA 116
Replication of DNA 118
Expression of Genetic Information 119
Colinearity of genes and proteins 120
The role of messenger RNA 120
The genetic code 121
RNA viruses and reverse transcription 124
Key Experiment
The DNA Provirus Hypothesis 125
Recombinant DNA 126
Restriction endonucleases 126
Generation of recombinant DNA molecules 128
Vectors for recombinant DNA 130
DNA sequencing 132
Expression of cloned genes 134
Detection of Nucleic Acids and Proteins 135
Amplification of DNA by the polymerase chain
reaction 135
Nucleic acid hybridization 137
Antibodies as probes for proteins 140
Gene Function in Eukaryotes 142
Gene transfer in plants and animals 142
Mutagenesis of cloned DNAs 144
Introducing mutations into cellular genes 146
Genome engineering by the CRISPR/Cas system 148
Interfering with cellular gene expression 148
Key Experiment
RNA Interference 151
SUMMARY AND KEY TERMS 153
QUESTIONS 154
REFERENCES AND FURTHER READING 155
 Contents ix

Chapter 5 Genomics, Proteomics, and Systems Biology 157

Genomes and Transcriptomes 157 Global analysis of protein localization 170
The genomes of bacteria and yeast 157 Protein interactions 171
The genomes of Caenorhabditis elegans, Drosophila Systems Biology 173
melanogaster, and Arabidopsis thaliana 159
Systematic screens of gene function 174
The human genome 160
Regulation of gene expression 175
The genomes of other vertebrates 160
Networks 176
Key Experiment
Synthetic biology 178
The Human Genome 161
Molecular Medicine
Next-generation sequencing and personal genomes 164
Malaria and Synthetic Biology 180
Global analysis of gene expression 166
SUMMARY AND KEY TERMS 181
Proteomics 167 QUESTIONS 182
Identification of cell proteins 167 REFERENCES AND FURTHER READING 183

PART II
The Flow of Genetic Information 185
Chapter 6 Genes and Genomes 187
The Structure of Eukaryotic Genes 187 Repetitive sequences 197
Introns and exons 188 Gene duplication and pseudogenes 201
Key Experiment Chromosomes and Chromatin 203
The Discovery of Introns 190
Chromatin 204
Roles of introns 192 Centromeres 208
Noncoding Sequences 194 Telomeres 213
Key Experiment SUMMARY AND KEY TERMS 214
The ENCODE Project 195 QUESTIONS 215
Noncoding RNAs 196 REFERENCES AND FURTHER READING 215

Chapter 7 Replication, Maintenance, and Rearrangements

of Genomic DNA 217
DNA Replication 217 Telomeres and telomerase: Maintaining the ends of
chromosomes 230
DNA polymerases 217
The replication fork 218 DNA Repair 232
The fidelity of replication 225 Direct reversal of DNA damage 233
Origins and the initiation of replication 226 Excision repair 235
x Contents

Translesion DNA synthesis 240 Antibody genes 245

Molecular Medicine Key Experiment
Colon Cancer and DNA Repair 241 Rearrangement of Immunoglobulin Genes 246
Repair of double-strand breaks 241 Gene amplification 252
SUMMARY AND KEY TERMS 254
DNA Rearrangements 243
QUESTIONS 255
Yeast mating types 244
REFERENCES AND FURTHER READING 256

Chapter 8 RNA Synthesis and Processing 259

Transcription in Bacteria 259 Regulation of elongation 283
RNA polymerase and transcription 260 Chromatin and Epigenetics 284
Repressors and negative control of transcription 263 Histone modifications 284
Positive control of transcription 264 Chromatin remodeling factors 289
Eukaryotic RNA Polymerases and General Histones and epigenetic inheritance 290
Transcription Factors 265 DNA methylation 292
Eukaryotic RNA polymerases 265 Noncoding RNAs 293
General transcription factors and initiation of RNA Processing and Turnover 295
transcription by RNA polymerase II 266
Processing of ribosomal and transfer RNAs 295
Transcription by RNA polymerases I and III 269
Processing of mRNA in eukaryotes 297
Regulation of Transcription in Eukaryotes 271 Splicing mechanisms 300
cis-acting regulatory sequences: promoters and Key Experiment
enhancers 271 The Discovery of snRNPs 303
Transcription factor binding sites 274 Alternative splicing 306
Transcriptional regulatory proteins 276 RNA editing 307
Key Experiment RNA degradation 309
Isolation of a Eukaryotic Transcription Factor 279 SUMMARY AND KEY TERMS 310
Structure and function of transcriptional activators 280 QUESTIONS 313
Eukaryotic repressors 282 REFERENCES AND FURTHER READING 313

Chapter 9 Protein Synthesis, Processing, and Regulation 317

Translation of mRNA 317 Protein misfolding diseases 341
Transfer RNAs 317 Molecular Medicine
The ribosome 319 Alzheimer’s Disease 342
The organization of mRNAs and the initiation of Enzymes that catalyze protein folding 343
translation 324 Protein cleavage 344
The process of translation 326 Glycosylation 346
Regulation of translation 332 Attachment of lipids 347

Protein Folding and Processing 338 Regulation of Protein Function 350

Chaperones and protein folding 338 Regulation by small molecules 350
 Contents xi

Protein phosphorylation and other modifications 351 The ubiquitin-proteasome pathway 357
Key Experiment Lysosomal proteolysis 358
The Discovery of Tyrosine Kinases 353 SUMMARY AND KEY TERMS 360
Protein–protein interactions 356 QUESTIONS 361
Protein Degradation 357 REFERENCES AND FURTHER READING 362

PART III
Cell Structure and Function 365
Chapter 10 The Nucleus 367
The Nuclear Envelope and Traffic between the Chromatin localization and transcriptional activity 382
Nucleus and the Cytoplasm 367 Replication and transcription factories 385
Structure of the nuclear envelope 367 Nuclear Bodies 386
Molecular Medicine The nucleolus and rRNA 387
Nuclear Lamina Diseases 371 Polycomb bodies: Centers of transcriptional
The nuclear pore complex 372 repression 391
Selective transport of proteins to and from the Cajal bodies and speckles: Processing and storage of
nucleus 373 snRNPs 391
Key Experiment SUMMARY AND KEY TERMS 392
Identification of Nuclear Localization Signals 374 QUESTIONS 394
Transport of RNAs 378 REFERENCES AND FURTHER READING 394
Regulation of nuclear protein import 380
The Organization of Chromosomes 381
Chromosome territories 381

Chapter 11 Protein Sorting and Transport

The Endoplasmic Reticulum, Golgi Apparatus, and Lysosomes
The Endoplasmic Reticulum 397
The endoplasmic reticulum and protein secretion 398
Targeting proteins to the endoplasmic reticulum 400
Key Experiment
The Signal Hypothesis 402
Insertion of proteins into the ER membrane 405
Protein folding and processing in the ER 411
Quality control in the ER 414
The smooth ER and lipid synthesis 418
Export of proteins and lipids from the ER 420
The Golgi Apparatus 421
397
Organization of the Golgi 422
Protein glycosylation within the Golgi 423
Lipid and polysaccharide metabolism in the Golgi 426
Protein sorting and export from the Golgi
apparatus 427
The Mechanism of Vesicular Transport 430
Experimental approaches to understanding vesicular
transport 430
Cargo selection, coat proteins, and vesicle budding 431
Vesicle fusion 435
Lysosomes 436
xii Contents
Lysosomal acid hydrolases 436
Molecular Medicine
Gaucher Disease 437
Endocytosis and lysosome formation 438
Chapter 12 Mitochondria, Chloroplasts, and Peroxisomes 447
Mitochondria 447
Organization and function of mitochondria 448
The genetic system of mitochondria 450
Molecular Medicine
Diseases of Mitochondria: Leber’s Hereditary
Optic Neuropathy 452
Protein import and mitochondrial assembly 453
Mitochondrial lipids 457
Transport of metabolites across the inner
membrane 457
Chloroplasts and Other Plastids 458
The structure and function of chloroplasts 459
Chapter 13 The Cytoskeleton and Cell Movement 479
Structure and Organization of Actin
Filaments 479
Assembly and disassembly of actin filaments 479
Organization of actin filaments 484
Association of actin filaments with the plasma
membrane 486
Microvilli 489
Cell surface protrusions and cell movement 490
Myosin Motors 493
Muscle contraction 493
Contractile assemblies of actin and myosin
in nonmuscle cells 498
Unconventional myosins 500
Microtubules 501
Structure and dynamic organization of
microtubules 501
Assembly of microtubules 505
Organization of microtubules within cells 506
Phagocytosis and autophagy 440
SUMMARY AND KEY TERMS 441
QUESTIONS 443
REFERENCES AND FURTHER READING 444
The chloroplast genome 461
Import and sorting of chloroplast proteins 461
Other plastids 465
Peroxisomes 467
Functions of peroxisomes 468
Peroxisome assembly 470
Molecular Medicine
Peroxisome Biogenesis Disorders 472
SUMMARY AND KEY TERMS 475
QUESTIONS 476
REFERENCES AND FURTHER READING 476
Microtubule Motors and Movement 508
Microtubule motor proteins 508
Key Experiment
The Isolation of Kinesin 509
Cargo transport and intracellular organization 512
Cilia and flagella 514
Reorganization of microtubules during mitosis 517
Chromosome movement 518
Intermediate Filaments 520
Intermediate filament proteins 520
Assembly of intermediate filaments 521
Intracellular organization of intermediate filaments 522
Functions of intermediate filaments: Keratins and
diseases of the skin 524
Key Experiment
Expression of Mutant Keratin Causes Abnormal
Skin Development 525
SUMMARY AND KEY TERMS 526
QUESTIONS 528
REFERENCES AND FURTHER READING 529
 Contents xiii

Chapter 14 The Plasma Membrane 531

Structure of the Plasma Membrane 531 Active transport driven by ion gradients 558
The lipid bilayer 531 Endocytosis 560
Plasma membrane proteins 534 Phagocytosis 560
Plasma membrane domains 540 Clathrin-mediated endocytosis 561
Transport of Small Molecules 544 Key Experiment
The LDL Receptor 564
Facilitated diffusion and carrier proteins 544
Ion channels 546 Clathrin-independent endocytosis 567
SUMMARY AND KEY TERMS 567
Active transport driven by ATP hydrolysis 553
QUESTIONS 568
Molecular Medicine
Cystic Fibrosis 557 REFERENCES AND FURTHER READING 569

Chapter 15 Cell Walls, the Extracellular Matrix, and Cell Interactions 571
Cell Walls 571 Cell–Cell Interactions 587
Bacterial cell walls 571 Adhesion junctions 587
Eukaryotic cell walls 573 Tight junctions 590
Gap junctions 591
The Extracellular Matrix and Cell–Matrix
Interactions 577 Molecular Medicine
Gap Junction Diseases 593
Matrix structural proteins 578
Plasmodesmata 594
Matrix polysaccharides 581
SUMMARY AND KEY TERMS 595
Adhesion proteins 582
QUESTIONS 596
Cell–matrix interactions 583
REFERENCES AND FURTHER READING 597
Key Experiment
The Characterization of Integrin 584

PART IV
Cell Regulation 599
Chapter 16 Cell Signaling 601
Signaling Molecules and Their Receptors 601 Eicosanoids 608
Modes of cell–cell signaling 602 Plant hormones 610
Steroid hormones and the nuclear receptor G Proteins and Cyclic AMP Signaling 611
superfamily 603
G proteins and G protein-coupled receptors 612
Nitric oxide and carbon monoxide 605
Key Experiment
Neurotransmitters 606 G Protein-Coupled Receptors and Odor
Peptide hormones and growth factors 607 Detection 613
xiv Contents

The cAMP pathway: Second messengers and protein Phospholipase C and Ca2+ 635
phosphorylation 615
Cyclic GMP 618
Receptors Coupled to Transcription
Factors 637
Tyrosine Kinases and Signaling by MAP Kinase, The TGF-b/Smad pathway 637
PI 3-Kinase, and Phospholipase C/Calcium NF-kB signaling 638
Pathways 619 The Hedgehog, Wnt, and Notch pathways 638
Receptor tyrosine kinases 619
Nonreceptor tyrosine kinases 622
Signaling Dynamics and Networks 641
Feedback loops and signaling dynamics 641
Molecular Medicine
Cancer: Signal Transduction and the Networks and crosstalk 642
ras Oncogenes 625 SUMMARY AND KEY TERMS 644
MAP kinase pathways 626 QUESTIONS 646
The PI 3-kinase/Akt and mTOR pathways 630 REFERENCES AND FURTHER READING 647

Chapter 17 The Cell Cycle 651

The Eukaryotic Cell Cycle 651 DNA damage checkpoints 669
Phases of the cell cycle 652 The Events of M Phase 670
Regulation of the cell cycle by cell growth and Stages of mitosis 670
extracellular signals 653
Entry into mitosis 673
Cell cycle checkpoints 656
The spindle assembly checkpoint and progression to
Regulators of Cell Cycle Progression 657 anaphase 677
Protein kinases and cell cycle regulation 657 Cytokinesis 678
Key Experiment Meiosis and Fertilization 679
The Discovery of MPF 658
The process of meiosis 679
Key Experiment Regulation of oocyte meiosis 682
The Identification of Cyclin 661
Fertilization 685
Families of cyclins and cyclin-dependent kinases 663
SUMMARY AND KEY TERMS 686
Growth factors and the regulation of G1 Cdk’s 665
QUESTIONS 688
S phase and regulation of DNA replication 668
REFERENCES AND FURTHER READING 688

Chapter 18 Cell Death and Cell Renewal 691

Programmed Cell Death 691 Signaling pathways that regulate apoptosis 698
The events of apoptosis 692 Alternative pathways of programmed cell death 702
Key Experiment Stem Cells and the Maintenance of Adult
Identification of Genes Required for Programmed
Tissues 703
Cell Death 694
Proliferation of differentiated cells 703
Caspases: The executioners of apoptosis 695
Stem cells 705
Central regulators of apoptosis: The Bcl-2 family 696

Medical applications of adult stem cells 711
Pluripotent Stem Cells, Cellular
Reprogramming, and Regenerative
Medicine 712
Embryonic stem cells 712
Key Experiment
Culture of Embryonic Stem Cells 713
Chapter 19 Cancer 723
The Development and Causes of Cancer 723
Types of cancer 723
The development of cancer 725
Causes of cancer 727
Properties of cancer cells 728
Transformation of cells in culture 732
Tumor Viruses 733
Hepatitis B and C viruses 733
Small DNA tumor viruses 734
Herpesviruses 735
Retroviruses 736
Oncogenes 737
Retroviral oncogenes 737
Proto-oncogenes 739
Key Experiment
The Discovery of Proto-Oncogenes 740
Oncogenes in human cancer 741
Answers to Questions 771
Glossary 783
Contents xv
Somatic cell nuclear transfer 715
Induced pluripotent stem cells 717
Transdifferentiation of somatic cells 718
SUMMARY AND KEY TERMS 719
QUESTIONS 720
REFERENCES AND FURTHER READING 721
Functions of oncogene products 745
Tumor Suppressor Genes 749
Identification of tumor suppressor genes 750
Functions of tumor suppressor gene products 753
Cancer genomics 757
Molecular Approaches to Cancer
Treatment 758
Prevention and early detection 759
Treatment 760
Molecular Medicine
Imatinib: Cancer Treatment Targeted against
the bcr/abl Oncogene 763
SUMMARY AND KEY TERMS 765
QUESTIONS 767
REFERENCES AND FURTHER READING 767
Illustration Credits 803
Index 805
Preface
Learning cell biology can be a daunting task because the field is so vast and
rapidly moving, characterized by a continual explosion of new information.
The challenge is how to master the fundamental concepts without becoming
bogged down in details. Students need to understand the principles of cell
biology and be able to appreciate new advances, rather than just memoriz-
ing “the facts” as we see them today. At the same time, the material must be
presented in sufficient depth to thoughtfully engage students and provide a
sound basis for further studies. The Cell provides a balance of concepts and
details designed to meet these needs of today’s students and their teachers.
The Seventh Edition of The Cell continues the central goal of helping stu-
dents understand the principles and concepts of contemporary cell biology
while gaining an appreciation of the excitement and importance of research
in this rapidly moving field. Our understanding of cell and molecular biology
has progressed in many ways over the last three years, and these important
advances have been incorporated into the current edition. Some of the most
striking advances have continued to come from progress in genomics and
proteomics. A new chapter in the current edition—Genomics, Proteomics,
and Systems Biology—focuses on these rapidly advancing areas and includes
discussion of the growing field of synthetic biology. Other notable advances
covered in the current edition include super-resolution microscopy, genome
editing by the CRISPR/Cas system, epigenetics, the organization of chro-
mosome domains in the nucleus, and an updated discussion of prions and
Alzheimer’s disease.
These and other advances have been incorporated into the Seventh
Edition of The Cell not only to provide current information but, even more
importantly, to give students a sense of the excitement and challenges of
research in our field. At the same time, I have sought to minimize details and
focus on concepts in order to ensure that The Cell remains an accessible and
readable text for undergraduates who are taking their first course in cell and
molecular biology. Distinguishing features of The Cell include the Molecular
Medicine and Key Experiment essays, which highlight clinical applications
and describe seminal research papers, respectively. Together with additional
experiments discussed throughout the text, these essays give the students
a sense of how progress in our field is made and a feel for how hypotheses
are framed and results interpreted. As in previous editions, each chapter
also includes several short “FYIs” designed to highlight areas of interest or
medical relevance, as well as a set of questions at the end of each chapter
with answers at the back of the book. In keeping with The Cell’s focus on
experimental analysis, many of these questions ask the student to think of
experiments or interpret results, as well as providing a review of the material.
A new feature of this edition is the addition of Data Analysis Problems to the
Instructor’s Resource Library. These problems present data and figures from
xviii Preface

original research papers and engage students in the analysis of experimental

methods and results. They also provide excellent material for discussions
and opportunities for student participation in active learning.
My most important goal in writing has been to convey the excitement
and challenges of research in contemporary cell and molecular biology. The
opportunities in our field are greater than ever, and I hope The Cell stimulates
today’s students to contribute to the research on which future texts will be based.

Acknowledgments
I am particularly grateful to Alexandra Adams for carefully reviewing the
entire text of the Seventh Edition of The Cell. The book has also benefited from
the comments and suggestions of reviewers, colleagues, and instructors who
used the previous edition. I am pleased to thank the following reviewers for
their thoughtful comments and advice:

Sage Arbor* Marian University

Rebecca Balish Miami University
Esther Biswas-Fiss Thomas Jefferson University
Edward Bonder Rutgers University
Lucinda Carnell Central Washington University
Xiao-Wen Cheng Miami University
Heather Cook* Wagner College
Gary Coombs* Waldorf College
Paul Davis University of Nebraska at Omaha
Jennifer Freytag* The Sage Colleges
Michael Garcia University of Missouri
David Gardner Marian University College of Osteopathic Medicine
Brittany Gasper Florida Southern College
Mark Grimes University of Montana
Karen Guzman Campbell University
Neil Haave* University of Alberta
Joyce Hardy* Chadron State College
Amber Heck Rocky Vista University College of
Osteopathic Medicine
Jose Hernandez Midwestern University
Peter Hoffman Notre Dame of Maryland University
Lisa Kadlec* Wilkes University
Ondra Kielbasa Alvernia University
Janet Kirkley Knox College
Jon Lowrance Lipscomb University
Kaushiki Menon Mt. San Antonio College
Vida Mingo* Columbia College
Craig Moyer Western Washington University
Perpetua Muganda North Carolina A&T State University
Laura Rhoads* State University of New York at Potsdam
Robert Roberson Arizona State University
German Rosas-Acosta The University of Texas at El Paso
D. Scott Samuels University of Montana
Ken Savage The University of British Columbia
Alexander Schreiber St. Lawrence University
Deborah Schulman Lake Erie College
 Preface xix

José Serrano-Moreno Western Washington University

Vishal Shah Dowling College
Mohammad Rafique Uddin LeMoyne–Owen College
Shannon Vandaveer University of Kansas
Thomas Wolkow University of Colorado, Colorado Springs
Kathleen Wood* University of Mary Hardin-Baylor
Robin Young The University of British Columbia
*Reviewed chapter(s) and Data Analysis Problems.

It is also a pleasure to thank our publisher for continuing support. Chelsea

Holabird did a superb editorial job. Jen Basil-Whitaker created a beautiful
design and page layouts. Andy Sinauer, Dean Scudder, and Christopher
Small were once again a real pleasure to work with.
Geoffrey M. Cooper
September, 2015
Organization and Features of
The Cell, Seventh Edition
The Cell has been designed to be an approachable and teachable text that
can be covered in a single semester while allowing students to master the
material in the entire book. It is assumed that most students will have had
introductory biology and general chemistry courses, but will not have had
previous courses in organic chemistry, biochemistry, or molecular biology.
Several aspects of the organization and features of the book will help students
to approach and understand its subject matter.

Organization
The Cell is divided into four parts, each of which is self-contained, so that
the order and emphasis of topics can be easily varied according to the needs
of individual courses.
Part I provides background chapters on the evolution of cells, methods for
studying cells, the chemistry of cells, the fundamentals of modern molecular
biology, and the fields of genomics and systems biology. For those students
who have a strong background from either a comprehensive introductory
biology course or a previous course in molecular biology, various parts of
these chapters can be skipped or used for review.
Part II focuses on the molecular biology of cells and contains chapters
dealing with genome organization and sequences; DNA replication, repair,
and recombination; transcription and RNA processing; and the synthesis,
processing, and regulation of proteins. The order of chapters follows the flow
of genetic information (DNA RNA protein) and provides a concise but
up-to-date overview of these topics.
Part III contains the core block of chapters on cell structure and function,
including chapters on the nucleus, cytoplasmic organelles, the cytoskeleton,
the plasma membrane, and the extracellular matrix. This part of the book
starts with coverage of the nucleus, which puts the molecular biology of Part
II within the context of the eukaryotic cell, and then works outward through
cytoplasmic organelles and the cytoskeleton to the plasma membrane and
the exterior of the cell. These chapters are relatively self-contained, however,
and could be used in a different order should that be more appropriate for
a particular course.
Finally, Part IV focuses on the exciting and fast-moving area of cell
regulation, including coverage of topics such as cell signaling, the cell cycle,
programmed cell death, and stem cells. This part of the book concludes with
a chapter on cancer, which synthesizes the consequences of defects in basic
cell regulatory mechanisms.
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 “This demand, which was accompanied by an expression
disapproving any policy of conquest, was repeated when the new
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hand of peace. Upon Germany, which has successfully defended
itself against superior forces, and which has frustrated the plan to
bring it to starvation, rests the duty of taking the first steps toward
peace. In the name of humanity and civilization, and recognizing the
favorable military position which our brave troops have won, we urge
the Government to try to end the struggle. We expect of our fellow
Socialists in other belligerent countries that they will make the same
demand upon their own governments.”

German Proposals for Peace

Letter of Dr. Bernhard Dernburg to American Newspapers, April

18, 1915.
1. The peace must be of a permanent nature. Dr. Dernburg.

2. The world is one interlocking family of nations. World dominion

is possible only with dominion on high seas. All the seas and
narrows must be neutralized permanently by common and effective
agreement guaranteed by all the Powers.
3. The free sea is useless without free cables. Cables must be
jointly owned by the interested nations, with a world mail-system.
Customs duties must be equal for all exports and imports, for
whatever destination and from whatever source. Preferential tariffs
with colonies are the basis of world-empire, and must not be
permitted.
4. International law should be codified, with guarantees to save all
neutrals from implication in wars in which they do not wish to take
part.
5. A natural commercial relationship between Germany and
Belgium must be established in workable form.
6. Germany should be permitted industrial expansion in such
foreign parts as need or wish for development.

Dr. Dernburg’s Speech at City Club, Cleveland, May 8, 1915.

1. Asks recognition of the truth that strong nations showing great
vitality and large increase are entitled to enough soil, air and water to
maintain and advance their growing population. The lack of such
proper adjustment of the conditions of the European Powers during
the last fifty years has been one of the primary causes for unrest in
Europe, and one of the principal dangers to the peace of the world.
2. Since no readjustment of the kind can take place in Europe on
national lines, it is necessary to seek the solution, first, by the
apportioning of all uncivilized parts of the globe, that is, by a
readjustment of colonial possessions, then by the creation of
spheres of influence and non-interference with nations who are
willing to take and to concede such spheres; further, by an open door
and equal opportunity policy all over the globe; and finally, by the
neutralization of all the seas and narrows, cables and overseas mails
of the world. This readjustment must be sanctioned by a simple and
codified international law, safeguarded so that it cannot be broken
without putting the infractor outside the pale of international
relationships, not only with the party attacked, but also with all the
parties remaining neutral. England must give up her rule of the seas,
which must be placed definitely in the hands of all the Powers of the
world. World trade must be free and all colonies neutralized. The
decision whether there is to be a free and neutralized sea or a
Chinese wall will also be decisive regarding the fate of Belgium. If
the sea remains fortified, there can be no choice for Germany except
to have her own sea fortresses as well, and since the only way of
getting out into the high sea would be by way of Belgium, there
would be no possibility of Germany’s considering the return of
Belgium to its former status.

PROF. DR. L. QUIDDE ON REAL GUARANTEES FOR A

DURABLE PEACE
I. The annexation of Belgium would prolong the Prof. Dr. L.
war indefinitely. Quidde.

II. The strength of the German Empire would decrease instead of

increase by the annexation of Belgium, in times of peace as well as
during the war.
The annexation of Belgium would destroy every outlook of a better
understanding between Germany and her present enemies, after the
war. It would make almost the whole rest of the world remain our
enemies and would call forth a coalition of all against one. Germany
need not foster illusions in this respect, if she only considers the
effect of the invasion into Belgium upon public opinion throughout
the world, especially in those neutral countries who were originally
Germany’s friends.
He who wishes to annex Belgium must have the courage to face
the fact that annexation will make the whole world our enemy for an
indefinite space of time and will completely isolate Germany
politically, so far as the feelings of the nations are to bring about
such isolation.
III. The annexation of Belgium is bound to bring about a new war.
It is evident that neither England nor France can allow Belgium to
be annexed by Germany as long as they do not wish to be
annihilated themselves. Especially England would have to prepare
retaliation with all the force that she can display, and it would be
easy enough for her to find allies to support her. One may differ
vastly on the subject of annexation, its advantages and drawbacks,
but one cannot deny that durable peace and annexation of Belgium
are two things absolutely incompatible.
Finally Prof. Quidde asks how it will be possible to make a durable
peace which at the same time guarantees the welfare of Germany.
This will be first of all a general removal of the causes that have led
to the war, followed by a thorough reorganization of Europe on lines
offering a better security for peace.
The first essentials for that reorganization are the “open-door” and
the “free sea,” which will have to be guaranteed by international
treaties.
One of the best grounded charges against International Law is,
that International Law is in many cases so hopelessly rudimentary
that the lack of precision forms a temptation to violate it. It is
necessary that a strong agitation for the development, perfection and
sanction of International Law should result from the experiences, the
causes and the course of this war.
 ED. BERNSTEIN ON PEACE TERMS

I
It is the vital interest of the majority of the Ed. Bernstein.
German nation, that the present war should end by
a peace treaty which, as to the rights and the relations of the nations,
is in conformity with the principles laid down in the program of the
German Social-Democrat Party and in the resolutions adopted by
their party-meetings and by the International Social-Democratic
Congresses.
Only a peace based on these principles will result in renewing the
friendly relations between Germany and the nations she is now at
war with, as soon and as thoroughly as possible.

II
The supreme principle, insisted upon in the program and the
resolutions of the Social-Democratic Party is the right of peoples to
decide their own fate, within the limits of international law.
The German Socialists consider it their duty to defend this
principle by all available means against any attack from any side
whatsoever. No nation or part of a nation having so far enjoyed
national independence, may be deprived of this right or see it
impaired; no territory may be annexed, when the annexation would
deprive the inhabitants of that right.
The Social-Democratic Party do not admit the right of conquest of
one nation over any other.

III
In the case of countries of European civilization, which have lived
under foreign rule, no territorial changes shall take place without a
referendum being taken of the inhabitants. This referendum should
be arranged and supervised by representatives of neutral States, so
as to insure perfect freedom in voting. Any inhabitant, who is of age
and has lived in the country for at least a year before the outbreak of
the war, shall have the right to vote.
In the interests of peace, all peoples of European civilization living
under foreign rule in sufficient numbers to form a community in the
international Concert, shall obtain political independence.
When a sufficient number out of subject peoples incorporated by
force in one State, desire to belong to another, they shall be given
the right to decide by vote as to which State they will belong.

IV
Transfer of territory outside of Europe shall only take place under
such conditions, as guarantee that the legal and material conditions
of such native population shall not be injured.

V
Nations can only be safeguarded against a renewal of war or wars
of retaliation by developing and strengthening international law.
In this respect the following means should be emphasized:
a. Development of the Hague Conference into a Permanent
International Conference for the Codification of International Law and
for International Arbitration. Concentration of the various Hague
institutions into a permanent international court, suitably divided into
branch courts.
b. All States to bring those differences they cannot themselves
peaceably solve, before the Court of Justice to be instituted by the
Hague Conference, where they will be settled either by mutual
agreement, conciliation or arbitration.
c. All signatory States to refrain from war or warlike measures till
the Court of Justice has examined the cause of war and till all
attempts to settle the difference in a peaceful manner, have proved
useless. Any State or Union resorting to hostilities contrary to these
rules to be treated as an enemy by all the others.
 d. The Parliaments to decide about war and peace. Secret treaties
to be abolished.
e. Development of International Law relating to the conduct of war
and the protection of the civil population. Abolition of the right of
capture at sea and of the right to levy war-contributions. No hostages
to be taken. Abolition of the system of reprisals against inhabitants of
an invaded country for acts of self-defense or defense of other non-
combatants. Permanent committees to watch the actions of
belligerents in occupied territories and the treatment of prisoners of
war and of civil prisoners interned in the enemy’s country.
f. Internationalization of transcontinental railways and of all
waterways connecting seas or lakes surrounded by different
countries, with the ocean.
g. Adoption of the principle of the Open Door for all Colonies,
Protectorates and for every territory which lies in the sphere of
influence of an European State.
h. These principles to be inserted into the constitutions of the
Powers.

BELGIUM
Whereas, Art. 2 already excludes any forcible annexation of
Belgian territory or any attack on the independence of Belgium by
another State, Germany has moreover invaded Belgium,
overpowered its army and occupied its territory without any
provocation from the side of Belgium and as the Chancellor has
himself admitted violating the neutrality of Belgium in defiance of the
law of nations. Germany having thus made her way into Belgium to
satisfy her own designs, beat down the resistance of the army and
occupied the country by force, Germany is therefore bound in honor
to evacuate Belgium immediately on the conclusion of peace, in
accordance with the solemn declaration, made on August 4, 1914,
by the German Ambassador, Prince Lichnowsky, to the English
Secretary of State, Sir Edward Grey, and to pay a full and ample
indemnity to the people of Belgium for the material and moral injury
which they have suffered.
 PEACE PROPOSALS AND PROGRAMS
5. FRANCE

French General Confederation of Labor

1. Federation of nations. C. G. T.

2. Compulsory arbitration of international disputes.

3. Independence of nationalities. Right of all peoples to dispose of
themselves to be safeguarded.
4. Suppression of secret diplomacy.
5. End of competitive armament.
6. Conference of organized labor forces of the world at same time
as conference of diplomats.
 PEACE PROPOSALS AND PROGRAMS
6. SWITZERLAND

Resolutions of Swiss Peace Society

At Annual Meeting, May 17, 1915.
1. The avoidance of any annexation or territorial Swiss Peace
changes which are in opposition to the interests Society.
and wishes of a population; a guarantee of
religious liberty, free speech and equality before the law, for the
minority.
2. The creation of a permanent organization in which all European
States shall be equally represented, for the purpose of safeguarding
the order, peace and safety of our portion of the earth.
3. The development of an international law organization by
continual Hague Conferences.

Swiss Committee for the Study of the Principles of a

Durable Treaty of Peace
President: Prof. Otto Nippold, Bern.
1. Participation of neutral nations in the Swiss Committee
settlement. for Study of
Peace.
2. Prohibition of secret treaties and agreements
between nations.
3. Participation of popular representative bodies in control of
foreign policy.
4. No annexation except after plebiscite of populations concerned.
5. Limitation of armaments to point of mere protection.
6. Manufacture of armaments to become State monopoly.
7. The States which participate in the settlement are to mutually
guarantee each other’s territories.
 8. Since the best guarantee for the preservation of world peace
lies in the creation of international law and custom, arbitration must
be substituted for war.
9. Disputed regions of the earth should be neutralized.
10. Free trade in all colonies.
 PEACE PROPOSALS AND PROGRAMS
7. HOLLAND

Nederlandsche Anti-Oorlog Raad

The Hague
Founded on the 8th of October, 1914
The Council is of opinion that the following Dutch Anti-War
principles are indispensable to attain a lasting Council.
peace:
1. Concert of the Powers instead of mutually opposed Alliances;
2. Limitation of armaments by international regulations;
3. Influence of the different Parliaments on the peace-treaty;
4. Avoidance of the dangers engendered by annexation or by
transfer of territory against the will of the population;
5. Removal of the obstructions to commerce or at least of
difference in treatment of the various nations in colonies and
settlements, according to international regulations.
6. New endeavors to promote compulsory arbitration and
compulsory inquiry of international differences.
 DIFFERENTIAL NEUTRALITY FOR AMERICA
One would prefer to think otherwise, but the truth probably is that
the future peace of the world, and the nature of international
organization depends a good deal less upon definitely conceived
plans like that of the League to Enforce Peace (however admirable
and desirable it may be to promote definite projects of that kind) than
upon the nature of the foreign policy which each nation individually
pursues. Disagreements between nations arise generally in
situations in which both sides honestly believe themselves to be in
the right. Most nations are honestly in favor of peace in general, and
would go to The Hague and assist in drawing up plans to maintain it;
yet each may be persisting in a line of conduct which, in its own view
entirely defensive and defensible, appears to another unwarrantably
aggressive. And when that is the case paper arrangements for
avoiding conflict are apt to break down.
So the most practical question for each of us for some time is
likely to be this: what will be the effect of our own country’s conduct
in its relations with other countries, upon the future peace and
international condition of the world? Or, to put the question in
another form: What can our country do, irrespective of what others
may do, to contribute to a more orderly international condition, saner
world politics?
America is of course concerned in the present war whether she
will or no. She may, by her material resources in supplies,
ammunition, credit, be largely influencing its decision. As part of the
problem of protecting her own rights, incidentally menaced by the
operations of the war, she has taken very solemnly a certain position
in international affairs. She has declared, for instance, that she
stands irrevocably for the protection of innocent non-combatant life
at sea in war time. She would undoubtedly stand as decisively for
certain lesser rights of trade and free communication on the seas as
well (in the past she has gone to war in their defense) but for the fact
that doing so against one belligerent would aid the cause of the other
guilty of still greater offenses.
 And if we look beneath diplomatically expressed claims into
unofficial, but unmistakably expressed public opinion, we find
America standing strongly for certain other rules of life between
nations—the right of each nation to national existence for instance—
like those violated in the invasion of Belgium.
Is America really serious in the stand thus made? Or is she going
to avow by her future policy, if not in words, that she will take no real
risk nor assume any real obligation in support of the principles she
has been maintaining diplomatically and by her clearly expressed
public opinion. Is she going to submit lamely, to the indignities and
violation of right involved in the massacre of her innocent non-
combatant citizens at sea?
I put the question in that form because it is generally a rhetorical
prelude to the demand for warlike action. And yet the American who
is moved by his country’s dignity and right to have thought this thing
out, as well as to have become angry about it, knows that warlike
action is perhaps the very last thing—though it may be the last thing
—which the situation calls for; and that warlike action alone would be
a betrayal of his country’s highest interests in the matter. If America
is really serious she must prepare herself—in public opinion, in
political education—for action of a different kind: for the
abandonment of certain traditions about freedom from entangling
alliances, for the assumption of risks and obligations which to most
Americans is to ask a great deal more than the mere act of going to
war.
Why will war of itself not suffice?
Suppose this country goes to war, over, for instance, the
submarine issue; and is finally entirely successful, so far as
defeating Germany is concerned. How do we then know that
America has got what she has been fighting for? Our demands at the
end of the war will be that American rights at sea shall be respected;
that, most particularly, non-combatants shall not be drowned by
attacks on merchantmen. Very good. Germany gives us her promise.
She has given it before. How do we know that it will be kept—either
by her or any other nation that in a future war may find a ruthless use
of the submarine the only weapon left to it against a power
commanding the sea? Can we hope that if we show now that we are
ready to fight “at the drop of the hat,” in future a hard-pressed
belligerent will be overawed by the great American navy? Then why
is not the belligerent we now propose to deal with held in check by
the combined navies of Great Britain, France, Russia, Italy, Japan
and Portugal? Again, when we have that promise at the end of our
victorious war how do we know that it will be kept, that we shall have
got what we have been fighting for?
And what of the American case against the Allies? Is America now
to surrender rights upon which she has insisted ever since she
became an independent State and which she once fought a war and
twice very nearly came to war to defend? Is America, in fighting
Germany to make the British Order in Council the basis of future sea
law, so that when say Japan goes to war with some other nation
America will have to submit to Japanese control of her trade and
communication with neutral States—even to mail and banking
correspondence—as she now submits to British control?
It is quite obvious that American claims have this difference from
those of the Allies: they, in so far as they are territorial can at the
peace be satisfied on the spot. America’s cannot. Hers depend
absolutely upon the establishment, after the war, of a different and
better international order; upon agreement as to what shall constitute
international law and some method of ensuring its observance.
Now has it not become evident that the present German-American
situation contains the elements of a great opportunity for America:
not only of putting an end to a situation humiliating for herself but of
creating a new state of world affairs out of which might grow—would
almost inevitably grow—the restoration of general peace on
conditions that civilization could accept?
But that result is certainly conditional on one thing: that American
diplomacy is great enough to make precedent, to be dangerously
honest to the point of dropping diplomatic make-believe and
breaking with diplomatic usage.
 Germany says in effect that she will make military sacrifices for the
purpose of respecting American neutral right, if America on her side
will reciprocally fulfil neutral obligation by insisting on the military
sacrifice from both belligerents; so that American rights are not made
a means of handicapping one party as against the other; are not
invoked in what Germany regards as so one-sided a fashion as to
become an arm for the use of one belligerent against the other.
Now it is quite within precedent, right and usage, to reply, as in the
past, to such a demand by diplomatic punctilio: “America cannot
discuss the behavior of one belligerent with the other,” and so forth
and so forth. The American government could make excellent
debating points and be diplomatically entirely correct.
But suppose, instead, it were undiplomatically honest and
unprecedentedly bold and said bluntly what every one knows to be
the truth: that because of the slowly acquired American conviction of
the badness of the German cause—the danger to civilization and
ourselves which this country has come to believe inherent in that
cause—it is impossible for America to enforce the law—or what
America holds to be the law—sharply against England, to take any
action which would seriously add to the chances of German victory;
to be, in other words, really neutral. Suppose America bold and
honest enough to avow the quite simple obvious truth that we are not
indifferent as to the outcome of the war and that in the long run our
conduct won’t be guided as though we were; that so long as we have
reason to believe German policy a menace it will encounter in one
form or another (not excluding necessarily even the military form) our
active or latent opposition.
And then, suppose that on top of that impossibly bold and honest
stand this country were further to announce that it can only act
effectively for the sea law Germany desires, and otherwise withdraw
its opposition, if Germany is prepared to reassure us as to her cause
by stating definitely that the terms upon which she is prepared to
discuss peace include such things as the evacuation of Belgium and
France and indemnification for damage done; the acceptance of the
international principles involved in the American claims; recognition
of the absolute right to existence of all States great and small;
readiness to enter, at least to the extent that others are ready, into
European or world arrangements for the guarantee of that right and
the mutual discussion and limitation of armaments; together with
such minor details as agreement to the appointment of an
international commission to enquire into the violation of the laws of
war on land and sea and the punishment of the individuals convicted
by that commission.
Once convinced that Germany stands for a policy such as peace
on those terms would imply, America could on her side (so this
impossibly honest diplomacy might make plain) stand effectively for
the freedom of the sea as against England if needs be at least to the
extent of upholding the Declaration of London; could assure
Germany that this country would never be reckoned among her
enemies, but on the contrary would co-operate with her in defense of
that equality of commercial opportunity in the world of which
Germany accuses her enemies of trying to deprive her.
Such a “Declaration of America’s International Position” as that
which I am here imagining would, in more precise terms, be about as
follows:
1. Though America since the outbreak of the war has done
everything possible to observe the form of neutrality which
international practise had heretofore imposed upon States not
actively participating in a war, the circumstances of the present
conflict have shown that the future protection of her own particular
interests are so identified with the maintenance of certain general
rules of international intercourse that in all future wars she will
differentiate in her treatment of the combatants. Thus in no case will
American resources be available for the military purposes of a
belligerent who had entered upon a war refusing to submit his case
to enquiry and the necessary delay, and to adhere to certain rules
necessary for the safeguarding of innocent non-combatant life.
The United States could not in consequence feel that her relations
with Germany could be placed upon a really sound foundation of
friendly cooperation until that country had
 (a) accepted the international principles (as for instance the
sanctity of non-combatant life) involved in the American claims and
the further principle that their violation is an unfriendly act towards
America whether American life and property are concerned or not;
(b) undertaken to evacuate Belgium, France and Serbia and
indemnify Belgium for damage done;
(c) agreed to the appointment of an international commission of
inquiry into the violation of the rights of non-combatants on land and
sea, with authority to assess damages, and to payment of any
damages in which Germany may be cast, and to punishment of
individuals convicted of offenses against the laws of war.
On the acceptance of these terms by Germany, America would
undertake:
A. Not to furnish military or naval aid to Germany’s enemies in this
war.
B. To become one of the guarantors of the integrity of Belgium.
C. In the event of the creation of new buffer States, to assist in the
maintenance of their inviolability by refusing to allow American
citizens to furnish their invader with supplies of any nature: by the
application, that is, of the principle of differential neutrality above
indicated.
D. To accord to German citizens in protectorates subject to
American control, commercial access on equal terms with American
citizens and to support by the differential neutrality already indicated
the policy of the open door in all protectorates and non-self-
governing territories. That is to say America would undertake not to
furnish military or naval aid to any power or group of powers that
refused to apply the principle of the open door in their protectorates,
and to prohibit the export of supplies or munitions to such powers in
their military operations.
E. To join, pari passu, with other powers in any arrangement for
enforcing the submission of international disputes to enquiry.
 Now whatever followed that announcement America and the world
would gain. If Germany refused she would by that prove that she
was still unchastened, not ready to surrender or modify her policy of
world hegemony. America then knows that her fears are justified.
She is definitely warned of a fact which sooner or later she will have
to face if it is really a fact. And it is obviously far better that it should
become patent to America (and the world) now, than later (after a
possibly patched up peace). Indeed, on grounds simply of sheer
national security America should attempt by some such means to
establish now, when Germany is relatively helpless so far as
damaging us is concerned, where she stands, what America faces. It
would enable her to make her future policy definite and objective.
But suppose Germany, realizing at last that it is impossible to
maintain a national policy which during the next generation or two
will have to meet not only the opposition of the Western democracies
of Europe and the potential forces of Russia, but all that North
America might during the next generation develop into, accepts?
What if the German government were pushed by the best elements
of the German people to take the opportunity thus so publicly offered
for putting themselves right with the world and starting afresh on a
more workable basis?
If that happened—which after all is the most probable thing of all—
America, without striking a blow, would have secured from Germany
the main thing for which the Western democracies are now fighting.
Not only would she have laid the foundation for the future protection
of her own sea rights in the only way in which finally they can be
protected—by an international law that is a reality because rooted in
a real international order—but she would have helped win the battle
of democracy by bringing about a discussion of terms before the
democratic nations have bled themselves white.
Never in history had a nation such an opportunity. But to take it
means breaking with routine, employing a new method, a new
manner; great governmental boldness, great political honesty. And
all that is, perhaps, too much to ask.
 But that is no reason why we should not face the fact that on those
conditions the opportunity is there. Nor why those most responsible
for the direction of American public opinion should not help the
nation to realize it.
Norman Angell.
 INDEX

Algeciras, 30.
Alliances, 135 ff, 144, 166;
prohibited, 94, 250, 266.
Alsace-Lorraine, autonomy of, 245, 260.
American School Peace League, program of, 267.
Angell, Norman, 33, 34, 82, 326.
Annexation, 76, 249, 306, 308, 311, 316, 322, 325.
Arbitration, 249, 251, 254, 262, 271, 306, 324;
compulsory, 262, 322, 325.
Armaments, export of, 266;
limitation of, 99, 124, 246, 248, 249, 250, 256, 262, 265,
266, 267, 271, 276, 277, 297, 300, 301, 306, 310, 322,
323, 325;
national manufacture of, 102 ff, 250, 265, 266, 267, 268,
269, 271, 277, 299, 300, 301, 324.
Armed Peace, 121.
Australian Peace Alliance, program of, 300.
Autonomy, 249, 254, 262, 275, 306, 318, 322.

Backward peoples, 22.

Balance of Power, 94 ff, 124, 265, 277, 301.
Bauer, Otto, 35.
Belgium, restoration of, 245, 260, 262, 274, 301, 320;
indemnity, 321;
and Germany, 58, 316, 320.