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Contents vii
CHAPTER 11 Computing Consequences 13.1 Late-acting

deleterious mutations are weakly selected 501
Sexual Selection 407
Computing Consequences 13.2 Alleles
11.1 Sexual Dimorphism and Sex 408 conferring early benefits and late costs can
11.2 Sexual Selection on Males: be adaptive 504
Competition 417 13.3 How Many Offspring Should an
11.3 Sexual Selection on Males: Individual Produce in a Given Year? 513
Female Choice 423 13.4 How Big Should Each Offspring Be? 517
Computing Consequences 11.1 Runaway 13.5 Conflicts of Interest between Life
sexual selection 430 Histories 522
11.4 Sexual Selection on Females 438 13.6 Life Histories in a Broader
11.5 Sexual Selection in Plants 441 Evolutionary Context 525
11.6 Sexual Dimorphism in Humans 444 Summary 530 • Questions 530
Summary 448 • Questions 448 Exploring the Literature 532 • Citations 532
Exploring the Literature 450 • Citations 451
CHAPTER 14
CHAPTER 12
Evolution and Human Health 535
The Evolution of Social Behavior 455
14.1 Evolving Pathogens: Evasion of the
12.1 Four Kinds of Social Behavior 456 Host’s Immune Response 537
12.2 Kin Selection and Costly Behavior 459 14.2 Evolving Pathogens: Antibiotic
Computing Consequences 12.1 Calculating Resistance 545
relatedness as the probability of identity 14.3 Evolving Pathogens: Virulence 548
by descent 461 14.4 Tissues as Evolving Populations
12.3 Multilevel Selection and Cooperation 471 of Cells 553
Computing Consequences 12.2 Different 14.5 Selection Thinking Applied to Humans 556
perspectives on the same evolutionary process 473 14.6 Adaptation and Medical Physiology:
12.4 Cooperation and Conflict 477 Fever 564
12.5 The Evolution of Eusociality 483 14.7 Adaptation and Human Behavior:
Summary 486 • Questions 487 Parenting 567
Exploring the Literature 488 • Citations 489 Computing Consequences 14.1 Is cultural
evolution Darwinian? 569
CHAPTER 13 Summary 575 • Questions 575
Aging and Other Life-History
Characters 491
13.1 Basic Issues in Life-History Analysis 493 CHAPTER 15
13.2 Why Do Organisms Age and Die? 495 Genome Evolution and the
Molecular Basis of Adaptation 581
15.1 Diversity among Genomes 582
15.2 Mobile Genetic Elements 586
15.3 The Evolution of Mutation Rates 591
15.4 Gene Duplication and Gene Families 594
15.5 The Locus of Adaptation in Natural
Populations 601
Summary 606 • Questions 606
viii Contents
Computing Consequences 18.1

Evolutionary trends 706
18.3 Taxonomic and Morphological
Diversity over Time 707
18.4 Mass and Background Extinctions 709
18.5 Macroevolution 719
18.6 Fossil and Molecular Divergence
Timing 727
Summary 730 • Questions 731
PART 4
CHAPTER 19
THE HISTORY OF LIFE 609 Development and Evolution 735
19.1 The Divorce and Reconciliation of
CHAPTER 16 Development and Evolution 736
19.2 Hox Genes and the Birth of Evo-Devo 738
Mechanisms of Speciation 609 19.3 Post Hox: Evo-Devo 2.0 744
16.1 Species Concepts 610 19.4 Hox Redux: Homology or Homoplasy? 763
16.2 Mechanisms of Isolation 616 19.5 The Future of Evo-Devo 764
16.3 Mechanisms of Divergence 623 Summary 765 • Questions 766
16.4 Hybridization and Gene Flow Exploring the Literature 766 • Citations 767
between Species 629
16.5 What Drives Diversification? 637
Summary 640 • Questions 641 CHAPTER 20
Exploring the Literature 642 • Citations 643 Human Evolution 769
20.1 Relationships among Humans
CHAPTER 17 and Extant Apes 770
20.2 The Recent Ancestry of Humans 780
The Origins of Life and 20.3 Origin of the Species Homo sapiens 790
Precambrian Evolution 645 Computing Consequences 20.1 Using allele
17.1 What Was the First Living Thing? 647 frequencies and linkage disequilibrium to date
17.2 Where Did the First Living Thing the modern human expansion from Africa 797
Come From? 655 20.4 The Evolution of Distinctive Human
17.3 What Was the Last Common Ancestor Traits 802
of All Extant Organisms and What Is Summary 807 • Questions 807
the Shape of the Tree of Life? 663 Exploring the Literature 809 • Citations 810
17.4 How Did LUCA’s Descendants Evolve Glossary 815
into Today’s Organisms? 678
Summary 683 • Questions 684 Credits 822
Index 830
CHAPTER 18
Evolution and the Fossil Record 691
18.1 The Nature of the Fossil Record 692
18.2 Evolution in the Fossil Record 696
Preface
E volutionary biology has changed dramatically during the 15 years we have

worked on Evolutionary Analysis. As one measure of this change, consider
that when the first edition went to press, the genomes of just five cellular
organisms had been sequenced: three bacteria, one archaean, and one eukaryote.
As the fifth edition goes to press, Erica Bree Rosenblum and colleagues reported
in the Proceedings of the National Academy of Sciences (110: 9385–9390) that they had
sequenced the genomes of 29 strains of a single species, the chytrid fungus Batra-
chochytrium dendrobatidis.This work was part of an effort to unravel the evolutionary
history of an emerging pathogen that has decimated amphibian populations around
the world and driven some species to extinction. The avalanche of sequence data
has allowed evolutionary biologists to answer long-standing questions with greatly
increased depth and clarity. In Chapter 20, Human Evolution, for example, we dis-
cuss a recent analysis of differences among genomic regions in the evolutionary
relationships among humans, chimpanzees, and gorillas. For some questions, the
answers have changed completely. In the fourth edition we noted that available
sequence data provided no support for the hypothesis that modern humans and
Neandertals interbred. But in the fifth edition we describe genomic analyses sug-
gesting that the two lineages interbred after all.
Evolutionary Analysis provides an entry to this dynamic field of study for
undergraduates majoring in the life sciences. We assume that readers have com-
pleted much or all of their introductory coursework and are beginning to explore
in more detail areas of biology relevant to their personal and professional lives.
Therefore, throughout the book we attempt to show the relevance of evolution
to all of biology and to real-world problems.
Since the first edition, our primary goal has been to encourage readers to think
like scientists. We present evolutionary biology not as a collection of facts but as an
ongoing research effort. When exploring an issue, we begin with questions. Why
are untreated HIV infections typically fatal? Why do purebred Florida panthers
show such poor health, and what can be done to save their dwindling population?
Why do mutation rates decrease with genome size among some kinds of organisms,
but increase with genome size among others? We use such questions to engage stu-
dents’ curiosity and to motivate discussions of background information and theory.
These discussions enable us to frame alternative hypotheses, consider how they
can be tested, and make predictions. We then present and analyze data, consider its
implications, and highlight new questions for future research. The analytical and
technical skills readers learn from this approach are broadly applicable, and will stay
with them long after the details of particular examples have faded.
New to This Edition
M any of the research areas we cover are advancing at a rate we would

not have dreamed possible just a few years ago.We have looked close-
ly at every chapter to both improve how we are teaching today’s
students and to thoroughly update our coverage.
ix
x Preface
• We have enhanced our traditional emphasis on scientific reasoning by includ-

ing a data graph, evolutionary tree, or other piece of evidence to accom-
pany the photo on the first page of every chapter. These one-page case studies
engage students as active readers and help them become skilled at working
with and interpreting data.
• We have enhanced our strong coverage of tree thinking by thoroughly
revising Chapter 4. Consistent with the ever-growing use of phylogenetic
analysis by scientists, we incorporate more phylogenies throughout the book.
Among the new examples are a tree-based discussion of evolution of ver-
tebrate eyes (Chapter 3); a new case study reconstructing the history of a
patient’s cancer (Chapter 14); and phylogeny-based reconstructions of the
fish-tetrapod transition, the dinosaur-bird transition, and the origin of mam-
mals (Chapter 18). Frequent practice at tree thinking helps students develop
this essential skill.
Every chapter contains something new. Most of the new material is from the
recent literature.
• Chapter 1 includes updated statistics on the status of the HIV pandemic, newer
thinking on how HIV causes AIDS, new data on the origin of HIV, and new
ideas and evidence on why HIV is lethal.
• Chapter 2 has a new organization featuring sections on evidence for micro-
evolution, speciation, macroevolution, and common ancestry; discussions of
why evolution at each level is relevant to humans outside of textbooks and
classrooms; evidence of macroevolution presented using evolutionary trees
showing the order in which derived traits are inferred to have evolved; and
several new examples, including a terrestrial fish that does not like to swim.
• Chapter 3 brings new evidence on the evolution of development in the beaks
of Darwin’s finches, a new example of exaptation featuring carnivorous plants,
and new coverage of the evolution of complex organs featuring a phylogeny-
based discussion of the evolution of vertebrate eyes.
• Chapter 4 has been completely rewritten to offer an improved introduction to
tree thinking; more detailed explanations of parsimony, maximum likelihood,
and Bayesian phylogeny inference; and new examples of phylogenies used to
answer interesting questions—such as identifying the surprising infectious
agent responsible for a sexually transmitted tumor in dogs.
• Chapter 5 includes a new section on kinds of variation, featuring new and
detailed examples of genetic variation and environmental variation; geno-
type-by-environment interaction; improved discussion of the mechanisms
and consequences of mutation; new examples of gene duplication; and cov-
ers rates and fitness effects of mutation in a dedicated section with new ex-
amples and data.
• Chapter 6 is bookended with a powerful new example in which genetic engi-
neers made a new gene, accurately predicted its effects on individuals carrying it,
introduced it into a population, and used population genetics theory to accurately
predict how its frequency would change over a span of 20 generations.
• Chapter 7 is bookended with a new example of conservation genetics involv-
ing the Florida panther. The chapter also includes a new example illustrating
the founder effect in Polynesian field crickets; improved coverage of the inter-
Preface xi
action of drift and selection, the neutral theory, and the nearly neutral theory;
and a new introduction to coalescence.
• Chapter 8 carries a new example—on Crohn’s disease in humans—showing
how linkage disequilibrium due to genetic hitchhiking can lead to spurious
associations between genotype and phenotype and a revised and updated sec-
tion on the adaptive significance of sex, featuring recent experiments using
C. elegans as a model organism.
• Chapter 9 has improved narrative coherence due to the inclusion throughout
the chapter of examples on the quantitative genetics of performance and prize
winnings in thoroughbred racehorses.
• Chapter 10 includes an improved primer on statistical hypothesis testing, using
research on the evolution of wild barley populations in response to a warming
climate, and a new example of comparative research involving color in feather lice.
• Chapter 11 improves our coverage of the evolution of female choice by
presenting the Fisher-Kirkpatrick-Lande model as the null hypothesis. New
examples and data consider Bateman’s principle in a hermaphrodite; female
preferences in genetically modified zebrafish; correlated displays and prefer-
ences in Hawaiian crickets; and sexual selection in humans.
• Chapter 12 features enhanced coverage, with examples, of the four basic kinds
of social behavior; improved coverage of kin selection and spite; a new section
on multilevel selection and the evolution of cooperation; and several data sets
on human social behavior.
• Chapter 13 has new examples on telomeres and aging; the evolution of meno-
pause; life history traits and biological invasion; and life history traits and vul-
nerability to extinction.
• Chapter 14 discusses new evidence, from genome architecture, on the origin
of influenza A; a new example using phylogenetic analysis to reconstruct the
history of a cancer; and updated coverage of diseases of civilization, including
a dramatic example from Iceland and new material on obesity.
• Chapter 15 has been completely rewritten, bringing new sections on the evo-
lution of genome architecture; the evolution of mutation rates and gene fami-
lies; and updated treatment of mobile genetic elements and the molecular basis
of adaptation.
• Chapter 16 features new sections on mechanisms of divergence; hybridization
and gene flow; and drivers of diversification.The chapter includes new examples
illustrating the application of species concepts; updated coverage of vicariance
in snapping shrimp; and new examples on mechanisms of isolation—including
temporal isolation in a moth and single-gene speciation in snails.
• Chapter 17 incorporates updated coverage of the effort to create self-replicating
RNAs and of the prebiotic synthesis of activated nucleotides.
• Chapter 18 has greatly expanded coverage of evolutionary transitions, fea-
turing phylogeny-based reconstructions of the fish-tetrapod transition,
the dinosaur-bird transition, and the origin of mammals; a new section on
taxonomic and morphological diversity over time; updated treatment of mass
extinctions, including the Permian-Triassic extinction; and a new section on
fossil and molecular divergence timing.
xii Preface
• Chapter 19 has been completely rewritten. It includes revised coverage of Hox

genes and detailed discussions of deep homology, developmental constraints
and trade-offs, and the evolution of novel traits.
• Chapter 20 discusses new evidence from complete genomes on incomplete
lineage sorting among humans, chimps, and gorillas, and on genetic differ-
ences between these species; new evidence, also from complete genomes, on
hybridization between modern humans and Neandertals and between mod-
ern humans and Denisovans; and updated coverage of the human fossil record
and the evolution of spoken language.
Hallmark Features
W hile fully updating this edition, we also maintained core strengths for
which this book is recognized.
• We continue to strive for clarity of presentation, ensuring each chapter con-
tains a coherent, accessible narrative that students can follow.
• We remain committed to strong information design and a tight integration
between the text and illustration program. Nearly all phylogenies are presented
horizontally, with time running from left to right, because research has shown
this makes it easier for students to interpret them correctly.
• Boxes contain detailed explorations of quantitative issues discussed in the main
text. These are called Computing Consequences, after physicist Richard Feyn-
man’s concise description of the scientific method: “First, we guess . . . No!
Don’t laugh—it’s really true. Then we compute the consequences of the guess
to see if this law that we guessed is right—what it would imply. Then we
compare those computation results to nature—or, we say, to experiment, or
experience—we compare it directly with observation to see if it works. If it
disagrees with experiment, it’s wrong.”
All chapters end with a set of questions that encourage readers to review the
material, apply concepts to new issues, and explore the primary literature.
Additional Resources for Instructors and Students
A
your needs.
t the Pearson Instructor Resource Center, you can download JPEG and
PowerPoint files containing all of the line art, tables, and photos from
the book. You can access versions with and without labels to best suit
A thorough test bank and TestGen software is available to help you gener-
ate tests. Each chapter has dozens of multiple choice, short answer, and essay
questions.
The updated Companion Website has been revised and updated to reflect the
new edition. The website can be found at: www.pearsonhighered.com/herron
Activities such as case studies and simulations challenge students to pose questions,
formulate hypotheses, design experiments, analyze data, and draw conclusions. Many
of these activities accompany downloadable software programs that allow students
to conduct their own virtual investigations. Students will also find chapter study
quizzes that allow them to check their understanding of key ideas in each chapter.
Preface xiii
Acknowledgments
E volutionary Analysis is a team effort.The book owes its existence and qual-
ity to the generosity and talents of a large community of colleagues,
students, and friends. They have reviewed chapters; made suggestions;
answered our questions; shared their photos, data, and insights; and lent us their
expertise in countless other ways. Getting to spend time with and learn from such
smart and interesting people is the best part of our job.
For the fifth edition we have had the great fortune to work with three extraor-
dinary contributors.
• Brooks Miner, Cornell University, wrote the entirely new Chapter 15 and
extensively revised and updated Chapter 16.
• Christian Sidor, University of Washington, thoroughly revised and expanded
Chapter 18.
• Jason Hodin, Hopkins Marine Station of Stanford University and University of
Washington, wrote the entirely new Chapter 19.
Mark Ong provided the beautiful and rational design of the new edition. Rob-
in Green designed and produced art that is both engaging and effective, and is
responsible for the coherent integration of the illustrations with the text.
The editorial, production, and marketing team at Pearson Education has offered
steadfast guidance and support: Michael Gillespie, Senior Acquisitions Editor—
Biology; Beth Wilbur, VP and Editor-in-Chief of Biology and Environmental
Science; Paul Corey, President—Science, Business, and Technology; Lauren Harp,
Executive Marketing Manager; Lori Newman, Production Project Manager;
Deborah Gale, Executive Director of Development—Biology; Laura Murray,
Project Editor; and Eddie Lee, Assistant Editor.
Our preparation of the fifth edition has been guided by thoughtful, detailed,
and constructive critiques by
Mirjana Brockett, Georgia Institute Kurt McKean, University at Albany

of Technology James Mullins, University of Washington
Jeremy Brown, LSU Christopher Parkinson, University of
Michael Emerman, University of Central Florida
Washington Yale Passamaneck, University of Hawaii
Charles Fenster, University of Maryland Bruno Pernet, California State
Matthew Hahn, University of Indiana University, Long Beach
Michael E. Hellberg, LSU Thomas Ray, University of Oklahoma
Christopher Hess, Butler University Doug Schemske, Michigan State
Gene Hunt, Smithsonian Institution University
Ben Kerr, University of Washington Billie J. Swalla, University of Washington
Craig Lending, SUNY Brockport Sara Via, University of Maryland
Carlos MacHado, University of Rebecca Zufall, University of Houston
Maryland
Finally, we extend a special thank you to Christopher Parkinson and his stu-
dents at the University of Central Florida and to Carol E. Lee and her students at
the University of Wisconsin. Both groups class-tested preliminary versions of the
chapters and provided insightful feedback that improved the final drafts.
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1
A Case for Evolutionary Thinking:
Understanding HIV
W hy study evolution? An incentive for Charles Darwin (1859) was

that understanding evolution can help us know ourselves. “Light
will be thrown,” he wrote, “on the origin of man and his history.”
The allure for Theodosius Dobzhansky (1973), an architect of our modern view
of evolution, was that evolutionary biology is the conceptual foundation for all
Multidrug therapies have, for
some patients, transformed
HIV from fatal to treatable.
Such therapies work best for
conscientious patients, but still
may fail. The data below are from
of life science. “Nothing in biology makes sense,” he said, “except in the light 2,800 patients on triple-drug
of evolution.” The motive for some readers may simply be that evolution is a therapy (Nachega et al. 2007).
required course. This, too, is a valid inducement.
Here we suggest an additional reason to study evolution: The tools and tech- 100
Percentage maintaining low
viral load (<400 copies/ml)
niques of evolutionary biology offer crucial insights into matters of life and death.
80
To back this claim, we explore the evolution of HIV (human immunodeficiency
virus). Infection with HIV causes AIDS (acquired immune deficiency syndrome)— 60
sometimes, as shown at right, despite triple-drug therapy. 40
Our main objective in Chapter 1 is to show that evolution matters outside of
labs and classrooms. However, a deep look at HIV will serve other goals as well. 20
It will illustrate the kinds of questions evolutionary biologists ask, show how an 0
< 60 60–79 80–99 100
evolutionary perspective can inform research throughout biology, and introduce Percentage monthly
concepts that we will explore in detail elsewhere in the book. prescriptions filled
1
2 Part 1 Introduction
HIV makes a compelling case study because it illustrates public health issues
likely to influence the life of every reader. It is an emerging pathogen. It rapidly
evolves drug resistance. And, of course, it is deadly. AIDS is among the 10 lead-
ing causes of death worldwide (Lopez et al. 2006; WHO 2008).
Here are the questions we address:
• What is HIV, how does it spread, and how does it cause AIDS?
• Why do therapies using just one drug, and sometimes therapies using multiple
drugs, work well at first but ultimately fail?
• Are human populations evolving as a result of the HIV pandemic?
• Where did HIV come from?
• Why are untreated HIV infections usually fatal?
While one of these questions contains the word evolution, some of the others As a case study, HIV will
may appear unrelated to the subject. But evolutionary biology is devoted to un- demonstrate how evolutionary
derstanding how populations change over time and how new forms of life arise. biologists study adaptation and
These are the issues targeted by our queries about HIV and AIDS. In preparation diversity.
to address them, the first section covers some requisite background.
1.1 The Natural History of the HIV Epidemic

AIDS was recognized in 1981, when doctors in the United States reported rare
forms of pneumonia and cancer among men who have sex with men (Fauci
2008). The virus responsible, HIV, was identified shortly thereafter (Barré-
Sinoussi et al. 1983; Gallo et al. 1984; Popovic et al. 1984). Nearly always fatal,
HIV/AIDS was devastating for those infected. But few physicians or researchers
foresaw the magnitude of the epidemic to come (Figure 1.1).
Indeed, many were optimistic about the prospects for containing HIV (Walk-
er and Burton 2008). Smallpox had been declared eradicated in 1980 (Moore et
(a) Figure 1.1 The HIV/AIDS
1.4 million pandemic The map (a) shows
the geographic distribution of
1.4 million 900,000 HIV infections. The color of each
830,000 region indicates the fraction of
300,000 adults infected with HIV (UNAIDS
230,000
2012b). The areas of the circles
Adult
4.0 million are proportional to the number
prevalence of individuals living with HIV
(% infected)
1.4 million (UNAIDS 2012b). The bars divide
5%
23.5 individuals living with HIV by sex
1% million and age (UNAIDS 2008). The
0.75 to 1% graphs (b) show the growth of
0.50 to 0.74% Number of people
53,000 the epidemic from 1990 to 2008
living with HIV
0.25 to 0.49% in four countries. Prepared with
data from UNAIDS (2008).
0 to 0.24% Percentage of infected people who
are women vs. men vs. children
% Women % Men % Children
(b)
United States United Kingdom South Africa India
Number of infected
people (millions)
1.2 0.09 6 3.0
0.8 0.06 4 2.0
0.4 0.03 2 1.0
0.0 0 0 0
1990 1996 2002 2008 1990 1996 2002 2008 1990 1996 2002 2008 1990 1996 2002 2008
Year
Chapter 1 A Case for Evolutionary Thinking: Understanding HIV 3
al. 2006), and vaccines and antibiotics had brought many other infectious diseases
under control. In 1984 the U.S. Secretary of Health and Human Services, Mar-
garet Heckler, predicted that an AIDS vaccine would be ready for testing in two
years. Actual events have, of course, played out rather differently.
HIV has infected over 65 million people (UNAIDS 2010, 2012a). Roughly
30 million have died of the opportunistic infections that characterize AIDS. The (a) Life expectancy at birth in
southern Africa (years)
disease is the cause of about 3.1% of all deaths worldwide (WHO 2008/2011). 70
AIDS is responsible for fewer deaths than heart disease (12.8%), strokes (10.8%),
and lower respiratory tract infections (6.1%)—common agents of death among
50
the elderly. But it causes more deaths than tuberculosis (2.4%), lung and other
respiratory cancers (2.4%), and traffic accidents (2.1%).
30
Figure 1.1 summarizes the global AIDS epidemic. The map reveals substantial 1950 1975 2000
variation among regions in the number of people living with HIV, the percent-
age of the population infected, and the proportion of infected individuals who (b) Number of people newly
infected each year (millions)
are women versus men versus children. The graphs show that the number of 4
people infected has peaked in some countries but continues to climb in others.
The epidemic has been most devastating in sub-Saharan Africa, where 1 in 20 2
adults is living with HIV (UNAIDS 2008). Worst hit is Swaziland, with 26% of
adults infected, followed by Botswana at 24%; Lesotho, 23%; and South Africa, 0
1990 2000 2010
18%. Across southern Africa, life expectancy at birth has dropped below 50, a
level last seen in the early 1960s (Figure 1.2a). The good news is that the annual Figure 1.2 Long-term trends
rate of new infections in sub-Saharan Africa has been falling for over a decade in HIV/AIDS (a) In southern
(UNAIDS 2012). This has meant that the global rate of new infections has been Africa, the epidemic has caused a
sharp reduction in life expectancy
falling as well (Figure 1.2b). at birth. From UNAIDS (2008). (b)
In developed countries, overall infection rates are much lower than in sub-Sa- Worldwide, the annual number
haran Africa (UNAIDS 2008). In western and central Europe, 0.3% of adults are of new infections has been fall-
infected. In Canada the rate is 0.4%, and in the United States it is 0.6%. For cer- ing since the late 1990s. Red line
tain risk groups, however, infection rates rival those in southern Africa. Among shows best estimate; gray band
shows range of estimates. From
men who have sex with men, the infection rate is 12% in London, 18% in New
UNAIDS (2012).
York City, and 24% in San Francisco (CDC 2005; Dodds et al. 2007; Scheer et
al. 2008). Among injection drug users, the infection rate is 12% in France, 13%
in Canada, and 16% in the United States (Mathers et al. 2008).
How Does HIV Spread, and How Can It Be Slowed?

A new HIV infection starts when a bodily fluid carries the virus from an infected
person directly onto a mucous membrane or into the bloodstream of an unin- An HIV infection can be
fected person. HIV travels via semen, vaginal and rectal secretions, blood, and contracted only from someone
breast milk (Hladik and McElrath 2008). It can move during heterosexual or else who already has it.
homosexual sex, oral sex, needle sharing, transfusion with contaminated blood
products, other unsafe medical procedures, childbirth, and breastfeeding.
HIV has spread by different routes in different regions (Figure 1.3, next page).
In sub-Saharan Africa and parts of south and southeast Asia, heterosexual sex
has been the most common mode of transmission. In other regions, including
Europe and North America, male–male sex and needle sharing among injec-
tion drug users have predominated. Certain activities are particularly risky. For
example, data on men who have sex with men in Victoria, Australia, show that
having receptive anal intercourse with casual partners without the protection of a
condom is a dangerous behavior. Individuals who report practicing it are nearly
60 times as likely to be infected with HIV as individuals who do not report prac-
ticing it (Read et al. 2007).
(a) Estimated new infections, by (b) Estimated new infections, by Figure 1.3 HIV’s main routes
likely mode of transmission: likely mode of transmission: of transmission in various
Cambodia Kenya Indonesia regions (a) From Pisani et al.
2002 1998 2002 U.S. 2006 Canada 2005 U.K. 2007 (2003). (b) From Hall et al. (2008),
Public Health Agency of Canada
(2006), Health Protection Agency
(2008). The authors of the re-
ports on Canada and the United
Kingdom note that many of the
Honduras Russia individuals who contracted HIV
Male–male sex (MMS) through heterosexual sex likely
2002 2002
MMS & IDU
Injection drug use (IDU)
did so in sub-Saharan Africa. See
Injection drug use Male–male sex
Sex work Casual heterosexual sex Heterosexual sex also UNAIDS (2008).
Heterosexual sex with a partner at high risk Other
Clinical studies in which volunteers are randomly assigned to treatment versus

control groups have identified medical interventions that reduce the rate of HIV
transmission. Use of antiviral drugs, for example, lowers the risk that infected
mothers will pass the virus to their infants by about 40% (Suksomboon et al.
2007). Antivirals are similarly effective in reducing transmission among men who
have sex with men (Grant et al. 2010). Circumcision reduces the risk that men
will contract HIV by about half (Bailey et al. 2007; Gray et al. 2007). Antiviral
vaginal gels are comparably beneficial for women (Abdool Karim et al. 2010).
The value of encouraging people to change their behavior is less clear. Be-
havioral change undoubtedly has the potential to curtail transmission. Consistent
use of condoms, for example, may reduce the risk of contracting HIV by 80%
or more (Pinkerton and Abramson 1997; Weller and Davis 2002). And there are
apparent success stories. In Uganda, for instance, a campaign discouraging casual
sex and promoting condom use and voluntary HIV testing is thought to have
80
New infections (1,000s)
substantially reduced the local AIDS epidemic (Slutkin et al. 2006; but see Oster
2009). On the other hand, the results of randomized controlled trials have been 60
somewhat disappointing. A study of over 4,000 HIV-negative men who have
40
sex with men in the United States offered extensive one-on-one counseling to
members of the experimental group and conventional counseling to the control 20
group (Koblin et al. 2004). As hoped, the experimental subjects engaged in fewer 0
risky sexual behaviors than the controls. However, the rates at which the experi- 76 84 92 00
mentals versus the controls contracted HIV were not statistically distinguishable. Year
There is clearly no room for complacency. The graph in Figure 1.4 tracks the Figure 1.4 New HIV infec-
number of new infections each year among men who have sex with men in the tions among men who have
United States. After falling from the mid 1980s to the early 1990s, the annual sex with men in the United
States From Hall et al. (2008).
number of new infections has since been rising steadily. The same thing seems to
be happening elsewhere (Hamers and Downs 2004; Giuliani et al. 2005). Results
of surveys suggest that the introduction of effective long-term drug therapies,
which for some individuals has at least temporarily transformed HIV into a man-
ageable chronic illness, has also prompted an increase in risky sexual behavior
(Crepaz, Hart, and Marks 2004; Kalichman et al. 2007).
What Is HIV?
Like all viruses, HIV is an intracellular parasite incapable of reproducing on its
own. HIV invades specific types of cells in the human immune system. The virus
hijacks the enzymatic machinery, chemical materials, and energy of the host cells
to make copies of itself, killing the host cells in the process.
1
HIV virion gp120 (surface protein)
RNA genome (2 copies) Reverse
transcriptase Mature virus 10
Integrase maturation
gp41
(anchor protein
Protease for gp120)
3 Protease
Fusion
2 HIV
Binding RNA 9
HIV reverse Budding
transcriptase HIV
HIV proteins
CD4 DNA
4 DNA 7
Coreceptor synthesis Translation
Host-cell 5 DNA
splicing 8
membrane HIV 6 Transcription
New
integrase virion
assembly
Host-cell Host-cell HIV
Host cell nucleus DNA mRNA
Figure 1.5 The life cycle of HIV (1, upper left) HIV’s (5) HIV’s integrase enzyme splices HIV’s DNA genome into the
extracellular form, known as a virion, encounters a host cell host cell’s genome. (6) HIV’s DNA genome is transcribed into
(usually a helper T cell). (2) HIV’s gp120 surface protein binds HIV mRNA by the host cell’s RNA polymerase. (7) HIV’s mRNA
first to CD4, then to a coreceptor (usually CCR5; sometimes is translated into HIV precursor proteins by host cell’s ribo-
CXCR4) on the surface of the host cell. (3) The HIV virion somes. (8) A new generation of virions assembles at the mem-
fuses with the host cell; HIV’s RNA genome and enzymes brane of the host cell. (9) New virions bud from the host cell’s
enter the host cell’s cytoplasm. (4) HIV’s reverse transcriptase membrane. (10) HIV’s protease enzyme cleaves precursors
enzyme synthesizes HIV DNA from HIV’s RNA template. into mature viral proteins, allowing the new virions to mature.
Figure 1.5 outlines HIV’s life cycle in more detail (Nielsen et al. 2005; Ganser-
Pornillos et al. 2008). The life cycle includes an extracellular phase and an intra-
cellular phase. During the extracellular, or infectious phase, the virus moves from
one host cell to another and can be transmitted from host to host. The extracel-
lular form of a virus is called a virion or virus particle. During the intracellular, or
replication phase, the virus replicates.
HIV initiates its replication phase by latching onto two proteins on the surface
of a host cell. After adhering first to CD4, HIV attaches to a second protein, called
a coreceptor. This leads to fusion of the virion’s envelope with the host’s cell
membrane and spills the contents of the virion into the cell. The contents include
the virus’s genome (two copies of a single-stranded RNA molecule) and two viral HIV is a parasite that afflicts
enzymes: reverse transcriptase, which transcribes the virus’s RNA genome into cells of the human immune
DNA; and integrase, which splices this DNA genome into the host cell’s genome. system. HIV virions enter host
Once HIV’s genome has infiltrated the host cell’s DNA, the host cell’s RNA cells by binding to proteins on
polymerase transcribes the viral genome into viral mRNA. The host cell’s ribo- their surface, then use the host
somes synthesize viral proteins. New virions assemble at the host cell’s membrane, cells’ own machinery to make
then bud off into the bloodstream or other bodily fluid. Inside the new virions, new virions.
HIV’s protease enzyme cleaves precursors of various viral proteins into functional
forms, allowing the virions to mature. The new virions are now ready to invade
new cells in the same host or to move to a new host.
A notable feature of HIV’s life cycle is that the virus uses the host cell’s own
enzymatic machinery—its polymerases, ribosomes, and tRNAs, and so on—in
almost every step. This is why HIV, and viral disease (a) Dendritic cells capture the virus and present bits of its proteins to
in general, is so difficult to treat. It is a challenge to naive helper T cells. Once activated, these naive cells divide to
produce effector helper T cells.
find drugs that interrupt the viral life cycle without also
disrupting the host cell’s enzymatic functions and thus Virus
causing debilitating side effects. Effective antiviral ther- Effector

helper
apies usually target enzymes specific to the virus, such T cells
as reverse transcriptase and integrase.
Naive
helper
How Does the Immune System React to HIV? T cell
A patient’s immune system mobilizes to fight HIV the
same way it moves to combat other viral invaders. Key
aspects of the immune response appear in Figure 1.6.
Sentinels called dendritic cells patrol vulnerable tis- Dendritic cell T-cell
receptor
sues, such as the lining of the digestive and reproduc-
tive tracts (Banchereau and Steinman 1998). When a (b) Effector helper T cells stimulate B cells displaying the same bits of
dendritic cell captures a virus, it travels to a lymph node viral protein to mature into plasma cells, which make antibodies
or other lymphoid tissue and presents bits of the virus’s that bind and in some cases inactivate the virus.
proteins to specialized white blood cells called naive
Effector
helper T cells (Sprent and Surh 2002). helper Plasma cells
Naive helper T cells carry highly variable proteins T cell B cell
called T-cell receptors. When a dendritic cell presents a
helper T cell with a bit of viral protein that binds to the
T cell’s receptor, the helper T cell activates. It grows Antibodies
and divides, producing daughter cells called effector (+) cytokines
helper T cells. Effector helper T cells help coordinate
Effector helper T cells also help activate killer T cells, which destroy
the immune response. host cells infected with the virus.
Effector helper T cells issue commands, in the form Effector Naive
of molecules called cytokines, that help mobilize a va- helper killer T cell
riety of immune cells to join the fight. They induce B T cell
(+)
cells to mature into plasma cells, which produce anti-
bodies that bind invading virions and mark them for
elimination (McHeyzer-Williams et al. 2000). They
activate killer T cells, which destroy infected host cells Effector
(Williams and Bevan 2007). And they recruit macro- killer T cells
phages (not shown), which destroy virus particles or kill
infected cells (Seid et al. 1986; Abbas et al. 1996).
Most effector helper T cells die within a few weeks. (c) Most effector T cells are short lived, but a few become long-lived
However, a few survive and become memory helper memory helper T cells.
T cells (Harrington et al. 2008). If the same pathogen Memory
invades again, the memory cells produce a new popula- Effector helper T cell
tion of effector helper T cells. helper
T cells
How Does HIV Cause AIDS?

As we noted earlier, HIV invades host cells by first
latching onto two proteins on the host cell’s surface.
The first of these is CD4; the second is a called a core-
Figure 1.6 How the immune system fights a viral infec-
ceptor. Different strains of HIV exploit different core- tion After NIAID (2003) and Watkins (2008).
ceptors, but most strains responsible for new infections
use a protein called CCR5. Cells that carry both CD4
and CCR5 on their membranes, and are thus vulner-
able to HIV, include macrophages, effector helper T cells, and memory helper T Macrophage
cells (Figure 1.7).
The progress of an HIV infection can be monitored by periodically measuring Effector
the concentration of HIV virions in the patient’s bloodstream and the concentra- helper T cells
tion of CD4 T cells in the patient’s bloodstream and in the lymphoid (immune
Memory
system) tissues associated with the mucous membranes of the gut. A typical un- helper T cells
treated infection progresses through three phases.
In the acute phase, HIV virions enter the host’s body and replicate explosively. Figure 1.7 Immune system
cells that carry both CD4 and
The concentration of virions in the blood climbs steeply (Figure 1.8). The con-
CCR5 on their membranes, and
centrations of CD4 T cells plummet—especially in the lymphoid tissues of the are thus vulnerable to HIV.
gut. During this time, the host may show general symptoms of a viral infection. Data from UNAIDS (2008).
The acute phase ends when viral replication slows and the concentration of viri-
ons in the bloodstream drops. The host’s CD4 T-cell counts recover somewhat.
Viral load CD4 T-cell count Figure 1.8 Typical clinical

(HIV RNA copies per ml of plasma) (percentage of pre-infection value) course of an untreated HIV in-
106 100 fection By the time the concen-
Circulating in blood
80
tration of CD4 T cells in the blood
Threshold for
105 stream falls below about 200 cells
onset of AIDS
60 per cubic millimeter, the patient’s
104 ~ 200 cells
40 per mm3 immune system begins to col-
103 20 lapse. After Bartlett and Moore
In lymphoid tissues of (1998), Brenchley et al. (2006),
102 0 gut and other mucosa Pandrea et al. (2008).
Phase: Acute Chronic AIDS
Phase: Acute Chronic AIDS
0 6 12 1 2 3 5 7 9 11 0 6 12 1 2 3 5 7 9 11
Weeks Years Weeks Years
Time since infection Time since infection
During the chronic phase, the patient usually has few symptoms. HIV con-
tinues to replicate, however. The concentration of virions in the blood may sta-
bilize for a while, but eventually rises again. Concentrations of CD4 T cells fall.
The AIDS phase begins when the concentration of CD4 T cells in the blood
drops below 200 cells per cubic millimeter. By now the patient’s immune sys-
tem has begun to collapse and can no longer fend off a variety of opportunistic
viruses, bacteria, and fungi that rarely cause problems for people with robust
immune systems. Without effective anti-HIV drug therapy, a patient diagnosed
with AIDS can expect to live less than three years (Schneider et al. 2005).
The mechanisms by which an HIV infection depletes the patient’s CD4 T
cells and undermines the patient’s immune system are complex. Despite a quarter
century of research, they remain incompletely understood (Pandrea et al. 2008;
Douek et al. 2009; Silvestri 2009). The simple infection and destruction of host
CD4 T cells may explain their precipitous loss during the acute phase of infec-
tion. But the immune system has an impressive capacity to regenerate these cells.
Furthermore, during the chronic phase no more than one CD4 T cell in a hun-
dred is directly infected. There must be more to the story.
Figure 1.9 (next page) outlines key events thought to lead from HIV infection
to AIDS (Appay and Sauce 2008; Pandrea et al. 2008; Douek et al. 2009; Silvestri
2009). HIV’s attack on the CD4 T cells in the gut (top) initiates a vicious cycle.
This attack not only destroys a large fraction of the patient’s helper T cells, it also
damages other tissues in the gut that help provide a barrier between gut bacteria
HIV infection Figure 1.9 A model for how

depletes CD4+ T HIV causes AIDS To read the
cells in gut; figure, start at the top, with HIV
damages gut
tissues. depleting CD4+ T cells in the gut.
Then proceed clockwise. Direct
Chronic infection effects of the virus are indicated
and inflammation by smaller pink arrows in the cen-
permanently
ter; indirect effects by larger tan
damage lymph
nodes and HIV infects arrows around the outside. After
Impaired gut
exhaust T-cell CD4+ T defenses allow Appay and Sauce (2008); Pandrea
proliferative cells in gut, translocation of et al. (2008); Douek et al. (2009);
capacity, leading bacteria and Silvestri (2009).
to diminished T- their products
cell supply. A steady supply of
from gut into
target cells allows
HIV induces bloodstream.
HIV to replicate
prolifically. immune Blood
activation. cells B cells
HIV replicates
most efficiently
in activated
CD4+ T cells.
x
Bacteria
Effector Memory
T-cell T cells
x T cells Naive
proliferation x Bacterial
gives HIV x T cells products in
x
x
more target x x bloodstream
cells. x x induce immune
x activation.
x
x x
Immune system activation causes effector T-cell proliferation.
and the bloodstream. The weakening of this barrier lets bacteria and their prod-
ucts move (translocate) from the gut into the blood (Figure 1.9, upper right).
The translocation of bacterial products into the blood triggers a high level of
immune activation, to which the HIV infection itself also contributes (Biancotto
et al. 2008). As we saw in Figure 1.6, activation of the immune system induces B
cells and T cells to proliferate. This aggressive immune response has benefits, at
least temporarily. For example, the anti-HIV killer T cells it yields help restrain
HIV’s replication. This and the production of new helper T cells allow the pa-
tient’s concentrations of CD4 T cells to recover somewhat (Figure 1.8). But in
the case of HIV, a strong immune response comes with heavy costs. The reason is HIV directly and indirectly
that HIV replicates most efficiently in activated CD4 T cells. In other words, the induces immune activation, then
immune system’s best efforts to douse the HIV infection just add fuel to the fire. replicates in activated immune
A major battleground in the ongoing fight between HIV and the immune system cells. When the ongoing
system is the patient’s lymph nodes (Lederman and Margolis 2008). The lymph battle damages the immune
nodes are, among other things, the places where naive T cells are activated. system to the point that it can
Chronic infection and inflammation eventually damages the lymph nodes irre- no longer produce enough T
versibly and exhausts the immune system’s capacity to generate new T cells. As cells to function properly, AIDS
the patient’s T-cell concentrations inexorably fall, the immune system loses its begins.
ability to fight other pathogens. The ultimate result is AIDS.
How might HIV be stopped before it leads to AIDS? The obvious answer is to
prevent it from replicating. The first drug to do so, azidothymidine, or AZT, was
approved for therapeutic use in 1987 (De Clercq 2009). Clinical experience with
AZT, and every antiviral developed since, brings us to the first of our organizing
questions. Why do single drugs offer only temporary benefits?
1.2 Why Does HIV Therapy Using Just One

Drug Ultimately Fail?
To fight a virus, researchers often look for drugs that inhibit enzymes that are
special to the virus and crucial to its life cycle. Such drugs should, in principle,
hobble the virus and have limited side effects. For HIV, potential targets include
the virus’s protease, integrase, and reverse transcriptase (see Figure 1.5). AZT, the
first drug approved to fight HIV, interferes with reverse transcriptase.
Figure 1.10 How AZT blocks

reverse transcription HIV’s
C
reverse transcriptase enzyme uses
OH nucleotides from the host cell to
RNA build a DNA strand complemen-
U A U C A C U A
G G
Reverse G tary to the virus’s RNA strand.
A Transcriptase C
AZT mimics a normal nucleotide
T
DNA A Nucleotides well enough to fool reverse tran-
A OH
OH scriptase, but lacks the attach-
OH OH ment site for the next nucleotide
T
C
T AZT-triphosphate in the chain.
N3
OH
OH
Figure 1.10 shows what reverse transcriptase does. The enzyme uses the virus’s
RNA as a template to construct a complementary strand of viral DNA. Reverse
transcriptase makes the DNA with building blocks—nucleotides—stolen from
the host cell.
The figure also shows how AZT stops reverse transcription. Azidothymidine
is similar in its chemical structure to the normal nucleotide thymidine—so simi- AZT is incorporated by HIV’s
lar that AZT fools reverse transcriptase into picking it up and incorporating it reverse transcriptase into the
into the growing DNA strand. There is, however, a crucial difference between viral DNA strand, where the
normal thymidine and AZT. Where thymidine has a hydroxyl group 1 9OH2, drug prevents the enzyme
AZT has an azide group 1 9N32. The hydroxyl group that AZT lacks is precisely from adding more nucleotides.
where reverse transcriptase would attach the next nucleotide to the growing However, alterations in
DNA molecule. Reverse transcriptase is now stuck. Unable to add more nucleo- the structure of reverse
tides, it cannot finish its job. AZT thus interrupts the pathway to new viral pro- transcriptase can make viral
teins and new virions. replication less vulnerable to
In early tests AZT worked, halting the loss of T cells in AIDS patients. The disruption.
drug caused serious side effects, because it sometimes fools the patient’s own
DNA polymerase and thereby interrupts normal DNA synthesis. But it appeared
to promise substantially slower immune deterioration. By 1989, however, after
only a few years of use, patients stopped responding to treatment. Their T-cell
counts again began to fall. What went wrong?
Does AZT Alter the Patient’s Physiology?

In principle, AZT could lose its effectiveness in either or both of two ways. One
is that the patient’s own cellular physiology could change. After it enters a cell,
AZT has to be phosphorylated by the cell’s own thymidine kinase enzyme to
become biologically active. Perhaps long-term exposure to AZT causes a cell to
make less thymidine kinase. If so, AZT would become less effective over time.
Patrick Hoggard and colleagues (2001) tested this hypothesis by periodically

checking the intracellular concentrations of phosphorylated AZT in a group of
patients taking the same dose of AZT for a year. The data refute the hypothesis.
The concentrations of phosphorylated AZT did not change over time.
Does AZT Alter the Population of Virions Living in the Patient?

The other way AZT could lose its effectiveness is that the population of virions
living inside the patient could change so that the virions themselves would be
resistant to disruption by AZT.
To find out whether populations of virions become resistant to AZT over
time, Brendan Larder and colleagues (1989) repeatedly took samples of HIV from
patients and grew the virus on cultured cells in petri dishes. Figure 1.11 shows
data for two patients the researchers monitored for many months. Each colored
curve in the graphs represents a particular sample. Each curve falls to show how
rapidly HIV’s ability to replicate is curbed by increasing concentrations of AZT.
Patient 1 Patient 2 Figure 1.11 HIV popula-

Months Months tions evolve resistance to AZT
100 100
of therapy of therapy within individual patients As
20 therapy continued in these pa-
16
Resistance of virions 11 11 tients, higher concentrations of
(% relative viability in 1
2
AZT were required to curtail HIV’s
presence of AZT) replication. Redrawn from Larder
50 50
et al. (1989).
0 0
0.001 0.01 0.1 1 10 0.001 0.01 0.1 1 10
Concentration Concentration
of AZT (␮M) of AZT (␮M)
Examine the three curves for Patient 1. Virions sampled from this patient after >10
AZT resistance (95% inhibitory dose (␮M)
he had been taking AZT for two months were still susceptible to the drug. At 10
moderate concentrations of AZT, the virions lost their ability to replicate almost 9
entirely. Virions sampled from the patient after 11 months on AZT were partially 8
7
resistant. They could be stopped, but it took about 10 times as much AZT to
6
do it. Virions taken after 20 months on AZT were highly resistant. They were
5
completely unaffected by AZT concentrations that stopped the first sample and 4
could still replicate fairly well at concentrations that stopped the second sample. 3
The data for Patient 2 tell the same story. Populations of virions within indi- 2
vidual patients change to become resistant to AZT. In other words, the popula- 1
tions evolve. 0.1
In many patients taking AZT, drug-resistant populations of HIV evolve with- 0
0 5 10 15 20 25
in just six months (Figure 1.12).
Months of therapy
What Makes HIV Resistant to AZT? Figure 1.12 In many patients,
What is the difference between a resistant virion versus a susceptible one? To AZT resistance evolves within
answer this question, consider a thought experiment. If we wanted to engineer six months This graph plots
resistance in 39 patients checked
an HIV virion capable of replicating in the presence of AZT, what would we
at different times. Redrawn from
do? We would have to modify the virus’s reverse transcriptase enzyme so that it Larder et al. (1989).
either avoids inserting AZT molecules into the growing DNA strand in the first
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he had been the only son and inherited a large fortune as well as the
lucrative and old-established business. It would not have been
difficult for him, in such a position, to have made a brilliant marriage;
had he so chosen, he might have entered the ranks of the
aristocracy, for more than one dowerless Belgravian maiden would
have welcomed him as a suitor.
But although he had plenty of business ambitions, he was not very
ambitious socially, considering his vast wealth. He had no desire to
enter a proud and impoverished family who might think they were
condescending when they allowed him to mate with their blue-
blooded daughter. For rich as he was, he had come of homely stock,
the founder of the great business having been a poor man of humble
origin who had begun on the lowest rung of the ladder.
So he followed his own inclinations. He went abroad for a long
holiday and returned with a wife, much to the astonishment of his
friends and acquaintances. And not very much was vouchsafed
about the antecedents of the lady who had become the wife of the
much-sought-after banker. The world was given to understand that
she was a woman of good family, but no very full details were given
until the arrival of Sir George Clayton-Brookes upon the scene, when
it was announced that a younger brother of his had married her
sister.
The long conversation between Archie Brookes and his aunt came
to an end presently, and then the young man took his departure. Like
Sir George, he was not greatly interested in this kind of function. He
did not belong to the exclusive clubs which opened their doors to his
fashionable uncle, but there were less pretentious establishments
which welcomed him. Like his relative, he was addicted to cards and
betting, and was only really happy when in the society of kindred
spirits.
Rosabelle and young Croxton spent some time together, while the
uncle and nephew had been discussing them, and Archie Brookes
had held that long conversation with his aunt. When young people
have got much to say to each other, it takes a long time to consume
an ice.
As they came back to the crowded rooms, the first person they
met was Rupert Morrice himself. He was a fine-looking, grey-
bearded man, carrying his fifty-five years well. The face was a little
hard, perhaps, the clear blue eyes were very keen, but the tones of
his voice showed that there was a very tender strain in his
composition. He gave a kindly glance to his niece, and addressed
the young man.
“I hope we shan’t be kept up too late, Dick; we have to be astir
betimes to-morrow, to open that safe.”
Rosabelle smiled her sunny smile. “That wonderful safe, uncle, of
which nobody but you and Dick knows the secret.”
The great financier indulged in a satisfied chuckle. “Yes, young
lady, you may smile, but I am very proud of it. It is ‘some’ safe, as the
Yankees would say, I can tell you.”
CHAPTER II
THE RIFLED SAFE
L ATER on, in the small hours, the young couple had a further tête-
à-tête. The members of the family had done their duty by their
several guests, and were at leisure to follow their own inclinations for
a while.
A celebrated violinist played the opening notes of a wailing melody
—the best of its kind was always a feature of the entertainments at
Deanery Street—and at the sound, Richard exchanged a meaning
glance with his sweetheart. Quietly they stole away to a secluded
corner where they could whisper away to their hearts’ content, and
were safe from interruption.
“Do you find it so difficult to screw up your courage to the sticking
point, you silly old Dick?” asked the girl presently in a low voice,
pursuing a conversation that had been proceeding for some little
time.
The young man smiled; the smile was a little rueful and apologetic.
“To tell the truth, my darling, I do. When I think of it in cold blood, it
seems such a daring thing to do.”
“‘Faint heart’—you know the rest,” said the girl, in a bantering
voice. “Well, Dick, if you can’t manage it, I shall have to throw my
maidenly modesty to the winds, and undertake it myself. I am not
afraid of my uncle, if you are.”
“But from my point of view, dear, you must admit it wants a lot of
pluck. A poor devil of a fellow with a couple of hundred a year of his
own, asking a millionaire to consent to a marriage with a niece whom
he is going to make his heiress. Wouldn’t ninety-nine men out of a
hundred kick me out of the house in double quick time?”
The smile on Rosabelle’s charming face grew sunnier than ever.
“But first of all, we will say, and it is the truth, that he is the
hundredth, not one of the ninety-nine. And then, it isn’t as if he didn’t
know. I don’t think we have kept our little secret very much to
ourselves, have we, Dick?”
“I am not so sure that he does know,” answered the still doubting
lover. “He is always so frightfully absorbed in his business, I think it
uses up all his faculties. We know we are in love with each other, but
I doubt if the fact is so patent to everybody as you think, my darling.”
“Rubbish!” cried the girl pertly. “Don’t you make any mistake about
Uncle Rupert being so wrapt up in business that he doesn’t observe
anything outside. Why, those keen eyes of his never let the most
trivial thing escape them. And I have often seen them resting on us
with a very intelligent expression. Take my word for it, Dick, he
knows what is going on, and he approves. You know how swiftly he
puts his foot down when he has a mind to. If he disapproved, he
would soon give me a very strong hint, or if he did not care to speak
to me himself, I should soon have a serious warning from auntie.”
Young Croxton was greatly encouraged by these words. He had a
firm belief in his sweetheart’s judgment and powers of penetration.
“That settles it then,” he said, speaking in a much more confident
tone. “I will tackle him to-morrow. I want to get it settled before we go
away to Mürren. Oh, my darling, if it is all right, as you think, shan’t
we have a lovely holiday?”
She gave his arm an affectionate squeeze. “And, as for all that
nonsense about having no money, why, I have no money either to
speak of. You have two hundred a year of your own, I have a
hundred. Well, Dick, if we were very wilful, I daresay we might be
brave enough to start on that, even if the worst were to happen. But
there, don’t let us think of that; I tell you it is going to be all right.”
He returned the affectionate squeeze she had given him with
interest. “By Jove, you do put courage into a fellow, little girl.”
“Not so little, if you please, Dick. I am rather above the average
height, you know. And if he is going to make me his heiress, as you
think, he doesn’t intend to leave you in the cold. He has treated you
like a son from the day you first came into the house. Everybody
knows how he worshipped your mother, and kept single all those
years because of her. I do not say he is not fond of auntie in a
steady, quiet way. But his other love was the sort that comes once in
a lifetime, and never again.” She bent her head very close and
whispered shyly in his ear. “He loved your mother, Dick, in the way
that you and I love each other, and of course he loves her son for her
sake.”
And after such a declaration, it is small wonder that these devoted
young lovers, knowing they were safe from observation, testified
their affection for each other in a long caress.
Later on, when the last car had rolled away, and the somewhat
weary host and hostess were alone, a brief conversation took place
between them on the subject of the young couple. It was begun by
Mrs. Morrice.
“You still approve of it, Rupert?” It was evident from these words
that the matter had been discussed between them before.
“Remember that Rosabelle is a very pretty girl, as well as a charming
one, and will have plenty of lovers in time.”
By these remarks it might be inferred that if Mrs. Morrice did not
offer actual opposition, she was quite ready to take a neutral attitude
in the matter.
Her husband did not beat about the bush in the least, he was
always a man who spoke out his mind unhesitatingly.
“Yes, I have thought it well out. If he is the man of Rosabelle’s
fancy, and everything points that way, I am quite willing he should
marry her. The moment he asks for my consent he shall have it.”
Mrs. Morrice heaved a gentle little sigh. “I know how fond you are
of Richard, that you could hardly be fonder of him if he were your
own son. Well, I own I am just a little sorry that her choice did not fall
upon Archie. It is not to be wondered at, for he is to me what Richard
Croxton is to you.”
Mr. Morrice frowned ever so slightly at the suggestion, but he
turned away his face quickly so that his wife should not see it. He
had wasted his heart upon Richard’s mother, and he could never
give another woman what he had given to her. But he was fond of
his wife, he appreciated her charm, her good qualities, the help she
gave him in the social side of his life, and he would not have pained
her for the world.
“If Rosabelle had set her heart upon Archie,” he said gravely, “I
cannot say for certain what my attitude would have been. I should
have hated to make her miserable, and yet—and yet I could not
have approved. I am glad that things are as they are. Archie has his
good qualities, no doubt; he is pleasant and amiable; I daresay he
would make a good husband. But, forgive me if I speak a little too
plainly, he is an incurable idler, and much too fond of pleasure—I
could not bear to see her married to a man of that stamp.”
There was a little quiver in the wife’s voice as she replied: “Are you
not just a little too hard upon poor Archie, Rupert? Remember, he
has not had the advantages of Richard’s training. If he had had you
for a tutor, how different he would have been. My brother-in-law is
not an ideal guardian of youth. An idler himself by the accident of
birth, and I fear by inclination, he does not see the necessity for work
in others.”
The great financier, whose life was one long strenuous working
day, from choice not necessity, shrugged his shoulders.
“Well, his uncle will leave him his money, that seems understood,
and therefore Archie has no need to work for a subsistence. But I
should think better of him if he took up some occupation, if only as a
hobby. Nothing saps a man’s character like the idle loafing life he is
leading now.”
There was a note of bitterness in Mrs. Morrice’s voice as she
replied to those uncompromising remarks.
“It is not at all certain that some day Archie will not have to work
for a living.”
Morrice looked at his wife in some surprise. “But Sir George is
credited with being a well-off man. You have told me the same
yourself.”
“He is well off perhaps now. But whether he dies rich or not will
depend upon what the gaming table and the race-course have left
him.”
Mr. Morrice pursed his lips, and his face grew very hard. It wore
the look that some of those who knew him in business dreaded to
see. Upright and of iron resolution himself, he had small pity for the
weak and self-indulgent. Above all, he loathed men who had made
ducks and drakes of their money, who threw it away in unprofitable
enterprises.
“I own that I have heard some rumours of this, that he bets too
highly, that he plays for too big stakes,” he said presently. “Well, it
would be a good thing if Master Archie could be removed from such
a corrupting influence.”
“Would to heaven that he could be.” There was a note of almost
anguish in the woman’s voice as she spoke, then she recovered
herself quickly, and added in a calmer tone: “But it is too late. His
uncle worships him, and he is devoted to his uncle.”
The morning came. Mr. Morrice was not going to his business
house; a client was calling on him in Deanery Street, and after that
visit had been paid, he was going to a jeweller’s in the West End for
a certain purpose. He had lately purchased some very fine and
expensive diamonds, which he had put away in readiness for an
important event—the birthday of his wife falling a week hence. He
was going to have these made up into a necklace and present it to
her upon the happy occasion. Like most women, she was
passionately fond of jewels, and though she already had plenty, he
knew she would be delighted to add to her store.
The client who was paying him a visit was coming to receive a
large sum of money, a million francs, which the financier had put for
safe custody in that wonderful safe to which allusion has been made.
Morrice and Richard breakfasted alone that morning at an early
hour, while the ladies stayed in bed to recover from the fatigue of the
previous evening.
Neither of the men spoke much during the progress of the meal.
The financier’s busy brain was at work upon his various schemes,
and he had almost forgotten that conversation a few hours earlier
with his wife concerning her brother-in-law and Archie Brookes.
Young Croxton was very preoccupied too. This was the day on
which, fortified by the encouraging counsels of his sweetheart, he
had resolved to screw up his courage and ask Morrice’s consent to
his betrothal to Rosabelle.
The two men from time to time looked at their watches, and at last
the elder rose with a quick, alert movement.
“It wants five minutes, Dick. Let us be going.” They went into
Morrice’s study, a spacious room, solidly furnished. In a corner stood
a big safe, from which, when the actual time arrived, they were going
to take the packet of French notes and the loose diamonds. Two
days previously they had shifted them to an easily accessible spot.
They stood before the formidable-looking receptacle, watches in
hand, and then with a simultaneous exclamation of “Now!” from
each, Morrice and his confidential secretary inserted their two
separate keys. The heavy door swung back, the financier advanced
his hand to the spot where the articles had been placed, and drew
back with a cry of dismay.
The packet of French notes, the canvas bag containing the loose
diamonds, had been removed from their hiding place, also a parcel
of private papers containing important secrets.
CHAPTER III
RICHARD IS DISMISSED
F OR an instant the two men stared at each other in blank

amazement as they stood in front of the big safe, the door of
which had been unlocked with such startling results.
The elder man recovered himself first. His was a strong, resolute
character, and it was always said of him by those who knew him
intimately, that no man could grasp the bearings of an unexpected
situation more readily. Croxton seemed dazed and stupefied beyond
the power of speech.
“But they were there, all of them, when we shifted them the other
morning, the packet of notes, the bag of diamonds, the parcel of
papers. You saw them, we both saw them.”
The young man’s voice was trembling as he answered: “We both
saw them, as you say, sir. They were there, right enough.”
The big financier took a great interest in the mechanism of safes; it
had always been one of his hobbies. He had tried half a dozen
different kinds during his business career, and in the present one he
was confident he had found the latest thing in ingenuity and safety.
In truth it was a marvel, and there was nothing else like it in all the
world. He had availed himself to the full of the resources of the
locksmith’s art, and had contributed a few practical suggestions as to
the actual mechanism himself. It had a marvellous time lock, the
secret of which was only known to himself and his secretary. The
time when the safe could be opened was automatically controlled by
the day of the month.
For example, if it was secretly set to open at nine o’clock on June
the twelfth, it would not open before nine plus six (the sixth month of
the year), plus twelve (the day of the month). Therefore, it would be
twenty-seven minutes past nine before the two keys could be
inserted, and then only for one minute. If that time passed, the safe
could not be opened till next day, and then not one minute but two
minutes later.
There was a long pause in which both men were thinking furiously.
Richard Croxton, recovering slowly from the shock, was beginning to
realize the awkwardness of the situation with regard to himself, and
to anticipate the thoughts that were forming themselves in the mind
of the man who had, up to the present, treated him more like a father
than an employer.
Gradually over Morrice’s countenance came that hard, grim look
which Richard had seen a few times during their association
together; notably in the early days when some gross act of
carelessness or inattention had aroused dissatisfaction and
subsequent anger.
“Well, what have you to say about it?” thundered the banker at
length. When he had once come to a conclusion he never beat about
the bush, but went to the point as straight as an arrow.
The unfortunate young man moistened his dry lips with his tongue.
It was an agonizing moment for him, and, engrossed as he was with
the terrible aspect of the situation, he could not help thinking of
Rosabelle and her heartening words uttered a few hours previously.
This was the day on which he had resolved to confess to her uncle
his love for the charming girl, and beg his consent to their betrothal.
In a few seconds this roseate prospect had been blotted out, and he
was confronting, not a kindly master and friend, but a stern and
angry judge.
“I have nothing to say, sir, except that I am innocent, and that
statement you do not look as if you were inclined to believe.”
The elder man emitted an angry exclamation, and the grim
expression grew grimmer as he gazed searchingly at the pale and
shaken young man.
“Richard Croxton, you are no fool, you can see the situation as it
presents itself to me, as it would present itself to anybody who knew
the circumstances. The secret of that safe is known only to us two,
you and I alone have access to it with our separate keys. Even
supposing for a moment, and it is a most wild supposition, that some
third party could have gained temporary possession of your key and
mine, and, after taking impressions of them, had duplicates made,
how was he to know the secret of the mechanism, the time at which
the safe would open. We saw the articles here two days ago; they
have been taken between yesterday and this morning.” He paused
and added significantly: “At that time when the safe could be
opened, I had left the house early, and was in my private room in the
city. You had work to finish here, and were to come down to me with
the report you were preparing at twelve o’clock.”
It was difficult for Croxton to preserve his faculties of thought as
the damning evidence grew and accumulated on him. But a ray of
light seemed to pierce suddenly through his benumbed brain.
“We breakfasted together at eight o’clock, sir, and you left directly
you had finished. After you had gone, I went up to my own room, and
remained till it was time for me to leave to join you in the city. I never
during that time entered this apartment. To that I am ready to swear;
I will take any solemn oath you care to dictate to me.”
Morrice seemed just a little staggered by the solemnity with which
these words were uttered, and for a second the hard, stern look
melted, but only for a second. His keen, logical mind at once
prompted the question.
“You say that you were in your own room practically all the time
you were alone. Is there any evidence you can bring forward to
corroborate this statement? Did Mrs. Morrice, Rosabelle, any of the
servants look in upon you during that period?”
The young man made a despairing gesture: “Alas, no. It is very
rarely that either Mrs. Morrice or Rosabelle pays me a visit when I
am at work. The servants are hardly ever about the house at that
time. And I know from what they said that both the ladies were out
very early on a shopping expedition. I don’t suppose that anybody
knew for certain whether I was here or in my own room. I have
nothing to offer you, sir, but my bare word, my solemn oath, if you
choose to accept it. But if I am what you appear to think me, my oath
would carry no more weight than my word. Again I say, much as
appearances are against me, inexplicable and astounding as the
whole thing is, before heaven I am not the thief who has stolen your
property.”
“Then if you are not the thief, I must be,” cried the irate financier
with bitter sarcasm, “though, I take it, the most suspicious detective
in the world would hardly dare to suspect me of purloining my own
money and diamonds.”
There was another long pause. Morrice walked up and down the
spacious room with long strides, the stern frown on his face now
deepening, now clearing a little, as his conflicting thoughts raced
through his brain. No doubt to him the brazen effrontery of the young
man seemed incredible, in view of the damning facts of the situation.
And that seemingly feeble excuse that he had been in his own room
during the time of the burglary, during the whole period between
breakfast and the moment when he left the house—did it hold water?
Was it a lie invented on the spur of the moment, or had it been
thought out beforehand to be produced at the moment of discovery.
And yet, if Richard were a cunning criminal, would he not have taken
precautions to secure some sort of alibi? The theft from the safe
would not have taken more than a minute, the articles were all
together, their removal would have taken no time. He could have
gone back to his room, rung the bell three or four times to summon a
servant on one pretext or another. It might not have been convincing
proof, for the robbery could have been accomplished so quickly, but
it would have been better than no proof at all.
But then the cleverest criminals made often very stupid mistakes,
and he could not believe the young man to be a hardened
malefactor. He had some secret vices that had never been
suspected, he had got into money difficulties; in his perplexity he had
taken advantage of the trust reposed in him, and yielded to a sudden
temptation.
And then, in the midst of his anger and disappointment, came
softening thoughts of the dead mother whom he had loved with such
a passionate devotion. Could he act towards her child as if he were a
stranger between whom there had been no tie save that between
employer and employed. The stern look melted away; he came up to
the stricken Richard and laid his hand upon his shoulder.
“Listen to me, Dick. You are the son of the woman whom I would
have given up everything else to make my wife, had she not
preferred your father to me. When you were left to the tender
mercies of the world, an orphan cast aside by your own family, with a
small pittance, enough to keep you from actual want, I came to your
rescue. I took you into my business; I took you into my house. I have
not perhaps told you very definitely of my future intentions, but you
can guess what they were likely to be. In a year or two I proposed to
give you a share of my business. I have noticed the attachment
between you and Rosabelle, who is very dear to me. I should have
put no obstacles in your way.”
The bitter irony of it all! But for this disastrous happening, what a
fair and golden future! The unhappy young man could not speak, but
inwardly he was suffering tortures. Those beautiful dreams of an
honourable and prosperous career, of a happy wedded life with the
charming girl he loved so dearly—all had vanished in those hateful
few moments!
“Listen to me, Dick,” went on the deep, resonant voice, and the
tone was now one more of sorrow than anger. “Abandon this
stubborn attitude of pretended innocence. Don’t regard me as the
stern and inflexible judge, ready to mete out deserved punishment,
but one who will incline to mercy, the mercy that all of us may stand
in need of some day. Your mother’s son cannot be naturally
dishonest, it is impossible. You have got into difficulties that I have
never suspected; in an evil hour your better instincts yielded to your
pressing needs, your fear of disgrace; and you did this base thing.
Confess your fault, make restitution if you can, if it is not too late, and
I will help you as I vowed to your mother I always would.”
A dreadful groan escaped from the tortured Richard. “You are one
of the best and kindest men on God’s earth; my mother whom you
so loved always told me so. If I were the guilty wretch you believe
me to be I would go on my knees and implore your pardon. But I am
not a thief, and I cannot restore what I have never taken.”
But Morrice, more than ever convinced of his obduracy, continued
to urge him, in tones that were almost pleading.
“There must of course be something between us that can never be
quite blotted out, in spite of repentance on the one side and
forgiveness on the other. I could never again put you in a position of
trust, for that fatal weakness might come over you once more. But I
would give you a post where temptation could not assail you. You
have spoken of your mother, so dear to us both. I implore you by the
memory of that beloved woman who, for aught we know, is even now
watching us from afar, to quit this stubborn attitude and confess the
truth.”
No reply came from the accused man, and the hard, stern look
came back to the banker’s face. At that moment the door of the room
slowly opened, and the charming vision of Rosabelle, looking her
sweetest and daintiest, stood framed in the opening.
“May I come in?” she cried in her fresh, girlish voice.
“Come in, my poor child,” was her uncle’s answer. “Come in;
something has happened that you will have to know sooner or later,
although I fear the knowledge may break your heart.”
White as death at these ominous words, she advanced into the
room, closing the door, her troubled glance changing from the stern,
set face of her uncle to the pallid countenance of her lover, the two
men who were the dearest to her in the world, loving the one with a
filial devotion that could not have been surpassed by a daughter, the
other with all the fervour of her ardent youth.
It was a painful scene. In a few trenchant words, the more weighty
from the cold, judicial tone in which they were uttered, Morrice
explained to her what had happened. She learned to a certain extent
the secret of that wonderful safe, about the protecting properties of
which she had so often laughingly rallied its owner, this wretched
safe which had worked the ruin of Richard, and now menaced her
own happiness.
She was too much dazed by the sudden and tragic happening to
do much more than grasp a few salient facts. The safe was opened
by two keys, one carried by each of the two men. They alone of all
the inmates of the house knew of its mechanism. That safe had been
opened, and certain valuable property extracted.
“But how could it be opened by one person, if it requires two
keys?” she cried, grasping at the first difficulty that presented itself to
her in her distress.
Mr. Morrice did not mince matters. “If I had a duplicate key of the
one carried by the other man, I could open it alone, and vice versa,”
he explained.
She understood the horrible suggestion, but her heart refused to
credit it. Of course she realized that her uncle would not steal his
own property, that would be a surmise altogether too ridiculous. But
it was equally impossible to believe that Richard, the man in whom
the great financier had placed such implicit trust, to whom her whole
soul went out in pity and yearning, should stoop to such a dastardly
act, with all the long and sinister preparations for its execution.
She stretched her hands out imploringly to her lover. “Richard, you
are no thief, nothing shall ever convince me of it,” she cried in a
voice of agony. “Deny it, deny it to us both. Say something that will
persuade him of the falseness of the accusation, of the injustice he is
doing you.”
The miserable young man was hardly less moved than herself. “I
have denied it, Rosabelle; I have offered to swear it, to take any oath
he may dictate to me. But he refuses to believe either word or oath. I
can do no more. Thank heaven, black as appearances are, you
believe that I am an honest man.”
“Oh yes, oh yes,” she cried brokenly. “I do not care a straw for
appearances, if they were twice as strong against you as they are. I
know you so well, my heart tells me that you have not done this
horrible thing.”
And then Morrice delivered his sentence. Incensed as he was at
what he considered the obstinacy of Croxton, he could not fail to be
moved by the girl’s passionate vindication of her lover.
“Richard Croxton, needless to say that from this day forth we are
strangers; my house can no longer give you shelter. For the sake of
one whose memory I shall always revere, I shall take no steps.
Nobody but Rosabelle and my wife will know the real reasons of your
departure. I am now going to the city to get money to replace that
which has been stolen. I shall go there and return here as quickly as
possible. I have no heart for any other business to-day. When I
return, let me find you gone. Later on I will invent some plausible
explanation of the severance of our relations, and give it out to those
who are interested.”
He turned on his heel without vouchsafing another glance at the
miserable man upon whom, up to the present, he had lavished
kindness and affection, strode through the hall, and a minute later he
had left the house.
The two wretched lovers were left alone, and when the door had
closed, the poor girl broke down, and threw herself into Richard’s
arms, sobbing bitterly.
CHAPTER IV
GIDEON LANE TAKES A HAND
“W HAT an awful day!” she cried when Richard had calmed her
a little, not that he was in much of a mood to administer
consolation to others. “And last night, when we talked of our future,
and I told you to pluck up your courage, I felt so gay and light-
hearted. Oh, Dick dear, it will kill me; but no, I must not let it do that.
We must both be brave, and strain every nerve to prove your
innocence.”
“It is indeed a tragic day,” corroborated her lover. “And, my darling,
but for this inexplicable mystery, it would all have been such plain-
sailing. In the midst of his reproaches, he paused to tell me that he
knew of our love for each other, and that he would have put no
obstacles in the way.”
The poor girl sobbed afresh at this. To have the cup of happiness
dashed down when it was so near her lips—could there be a more
poignant disappointment? But presently, she rallied and dried her
tears, and inquired his plans for the future. Morrice had ordered him
to quit the house before he returned to it. There could be no
disobeying that command.
“I have often spoken to you of the dear old soul who was first my
mother’s nurse and then mine. My grandfather left her a small
annuity as reward for her faithful services to his family. She has a
tiny little cottage at Petersham, near Richmond. She will take me in
until I have collected my thoughts sufficiently to decide upon my
future.”
“And I shall come and see you there, Dick,” cried the girl eagerly,
“even though you are forbidden this house.”
“My darling, you must not do anything without your uncle’s
sanction. In certain moods, he is a stern and hard man.”
Richard felt that life, in a way, was over for him, but for this brilliant
young creature it was only just beginning. Touched as he was by her
faith in him, he knew that it would be folly for her to cling to a man
over whom hung the shadow of disgrace. As yet, he could not wound
her feelings by telling her so. But presently, when he had recovered
himself sufficiently to think and plan, he would pass quietly out of her
life.
“He may be stern and hard at times, but he is always just,” said
Rosabelle. “He will not think the less of me because I refuse to
believe you guilty. Why, Dick, I know you so well,” she added
impetuously. “I would not credit the evidence of my own eyes against
your word. If these things had been found in your pockets and you
had denied you stole them, I would have believed you, and known
the real thief had put them there for the purpose of incriminating
you.”
Young Croxton smiled a wan smile at his sweetheart’s
vehemence. Can anything equal the blind faith of a woman in the
man she loves? It is one of those qualities amongst many which they
must surely derive from a divine source.
“He is sore and angry over his loss now,” went on the beautiful girl.
“In a day or two he will calm down, and see that he has been too
hasty in his judgment.”
“I have never known him angry over losses, and hardly a year
goes by that he does not make heavy ones,” answered Richard
sadly. “No, to do him justice, what has cut him to the quick is the
supposed discovery of my unworthiness.”
Half an hour later, Richard Croxton had left the familiar house in
Deanery Street which had sheltered him so long. His sweetheart
bade him a tearful farewell, and Mrs. Morrice, to whom the young
couple explained the terrible happenings of the morning, showed
considerable emotion. In her heart, she would have preferred her
nephew, Archie Brookes, as a husband for Rosabelle, but she had
always been very fond of Richard, and stoutly expressed her belief in
his innocence.
A taxi bore him swiftly to the neat little ivy-covered cottage at
Petersham, where he received a hearty welcome from his old nurse,
a comely old woman verging upon her seventieth year, but hale and
vigorous for her age. To her he did not explain the actual truth, but
simply stated that circumstances had suddenly arisen which
rendered necessary the severing of his connection with Mr. Morrice.
The good, simple old soul said little, but she was very upset at the
news. She knew very well that the great financier had treated him
like a son, and that this sudden separation meant the ruin of his
bright prospects.
“And Miss Rosabelle?” she inquired anxiously. Hitherto he had
kept few secrets from the faithful and sympathetic old woman, who
had long ago learned the history of his love affair.
“She will come and see me, dear old nurse, that is to say, if her
uncle does not expressly forbid her.”
Mrs. Hart, such was the name of this faithful old servant, made no
comment upon this significant remark. It crossed her mind that it was
more than probable Richard’s departure had been caused by this
very love-affair; that fond as he was of him, the wealthy financier had
resented his attentions to his niece, who, in the course of time, would
be a considerable heiress.
It may be observed in passing that the same opinion was held in
the servants’ hall at Deanery Street, where the young man’s sudden
exit had naturally aroused a tremendous amount of interest. It had
also occurred to Morrice, desirous of keeping the true facts to
himself, more perhaps from respect for the dead than tenderness to
the living, that he might get his wife to give some hints which would
produce the same impression amongst their acquaintances.
True to her promise, in a few days Rosabelle arrived at the ivy-
covered cottage, having warned her lover, in a letter received by the
first post in the morning, of her visit.
He noticed that she drove up in a taxi, not, as was usual, in one of
her uncle’s cars. He was, of course, overwhelmed with joy at seeing
her so soon, but he was very anxious that the fidelity to himself
should not entail disastrous consequences to her own fortunes. So
the first question he asked was whether Mr. Morrice knew of her
visit.
“Everything is straight and above-board, dear Dick,” was the girl’s
answer. “I had a long talk with him yesterday morning at his early
breakfast. I got up early myself in order to seize a chance of finding
him alone. He seemed very sad and preoccupied, but he was not as
stern and harsh as on that dreadful day. I told him a lot of things as
they came into my head, how dearly we loved each other, how we
had fallen in love from the first day we met—that no matter if all the
world turned against you, I should still be faithful, that my one great
object was that you should take steps to get yourself cleared and
discover the real criminal.”
“And what did he say to all this?” asked the young man eagerly. “I
can guess, my darling, that you pleaded very well.”
“He listened very attentively, and was very quiet for a long time.
When I had finished, he asked me if I wished him to send for
detectives from Scotland Yard. I hastily said that I did, and that I was
sure you would wish it too. ‘My poor child, you don’t know what you
are talking about,’ was his answer. ‘The certain result of that would
be that the man in whom you believe would be arrested, and once
having taken the case up, I could not drop it, I should be bound to
prosecute.’ That scared me dreadfully, you may be sure. His final
words were spoken in a very sad voice. ‘Let sleeping dogs lie, my
poor wronged Rosabelle. Richard Croxton through his own act has
passed away from my life, as he must pass away from yours. You
are young, and in time your grief will heal, and some day you will
meet a man worthy of your love.’”
The young man’s head sunk on his breast. Yes, Mr. Morrice was
right. Appearances were too black against him; if the authorities
were called in, arrest would be sure to follow.
The girl went on in a low, tearful voice. “I told him that the day to
which he looked forward would never come, that if I could not marry
you, no other man should be my husband. And then, Dick, I ended
with the boldest thing I had said yet—I am pretty brave as a rule but I

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CHAPTER 11 Computing Consequences 13.1 Late-acting

Computing Consequences 18.1

E volutionary biology has changed dramatically during the 15 years we have

New to This Edition

M any of the research areas we cover are advancing at a rate we would

• We have enhanced our traditional emphasis on scientific reasoning by includ-

• Chapter 19 has been completely rewritten. It includes revised coverage of Hox

Additional Resources for Instructors and Students

Mirjana Brockett, Georgia Institute Kurt McKean, University at Albany

W hy study evolution? An incentive for Charles Darwin (1859) was

1.1 The Natural History of the HIV Epidemic

1.2 0.09 6 3.0

0.8 0.06 4 2.0

0.4 0.03 2 1.0

How Does HIV Spread, and How Can It Be Slowed?

Clinical studies in which volunteers are randomly assigned to treatment versus

causing debilitating side effects. Effective antiviral ther- Effector

How Does HIV Cause AIDS?

Viral load CD4 T-cell count Figure 1.8 Typical clinical

HIV infection Figure 1.9 A model for how

Immune system activation causes effector T-cell proliferation.

1.2 Why Does HIV Therapy Using Just One

Figure 1.10 How AZT blocks

Does AZT Alter the Patient’s Physiology?

Patrick Hoggard and colleagues (2001) tested this hypothesis by periodically

Does AZT Alter the Population of Virions Living in the Patient?

Patient 1 Patient 2 Figure 1.11 HIV popula-

F OR an instant the two men stared at each other in blank

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