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Readable and highly illustrated, Robbins and Cotran Pathologic Basis of Disease, 10th Edition presents an in-depth, state-of-the-art overview of human diseases and their cellular and molecular basis. This best-selling text delivers the latest, most essential pathology knowledge in a readable, interesting manner, ensuring optimal understanding of the latest basic science and clinical content. More than 1,000 high-quality photographs and full-color illustrations highlight new information in molecular biology, disease classifications, new drugs and drug therapies, and much more. This superb learning package also includes an enhanced eBook with a full complement of ancillary content on Student Consult.
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Year:
2020
Edition:
10
Publisher:
Elsevier
Language:
english
Pages:
1328
ISBN 13:
9780323609920
Series:
Robbins Pathology
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Thanks man!!! That is good quality of latest edition.
06 November 2020 (16:31) 
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Thank you so much. Latest edition much needed.
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thanks very much,good edition
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Thank you! Excellent copy. Index is missing though.
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Robbins
and
Cotran.
Where an effective understanding of disease begins.
A current and accurate understanding of pathophysiology is integral to effective practice in every specialty. No
source delivers that understanding better than the Robbins and Cotran family! Robbins Basic Pathology, Robbins
Essential Pathology, and their many companion resources provide a clear, up-to-date explanation of disease
mechanisms you need to succeed.

Robbins Basic Pathology, 10th Edition
ISBN: 9780323353175

Key Features:
• Excellent art program boasts high-quality photomicrographs,
gross photos, and radiologic images to supplement the
world-class illustrations.
• Bulleted summary boxes provide quick access to key information and
easy review of key concepts.
• Highlights pathogenesis, morphology, and pathophysiologic
content throughout.

Robbins Essential Pathology, 1st Edition
ISBN: 9780323640251

Key Features:
• The most concise Robbins text available, providing high-quality content and a
case-based approach in a focused, multimedia learning package for coursework
and exam preparation.
• Focuses on the core knowledge of disease mechanisms and essential clinical
aspects that medical students need to know.
• Features more than 500 images and tables that illustrate key disorders
and concepts.

Explore the entire Robbins and Cotran Family at
elsevierhealth.com/pathology

ROBBINS&COTRAN

PATHOLOGIC
BASIS OF DISEASE

RO B B I N S
& C OT R A N

PATHOLOGIC
BASIS OF DISEASE
TENTH EDITION

Vinay Kumar, MBBS, MD, FRCPath

Alice Hogge and Arthur A. Baer Distinguished Service Professor of Pathology
Biologic Sciences Division and the Pritzker Medical School
The University of Chicago
Chicago, Illinois

Abul K. Abbas, MBBS

Emeritus Professor and Chair
Department of Pathology
University of California San Francisco
San Francisco, California

Jon C. Aster, MD, PhD

Michael Gimbrone Professor of Pathology
Brigham and Women’s Hospital and Harvard Medical School
Boston, Massachusetts
Associate Editor

Jerrold R. Turner, MD, PhD
Profe; ssor of Pathology and Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
W I T H I L L U S T R AT I O N S B Y :

James A. Perkins, MS, MFA

Distinguished Professor of Medical Illustration
Rochester Institute of Technology
Rochester, New York

Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
ROBBINS & COTRAN PATHOLOGIC BASIS OF DISEASE, TENTH EDITION
INTERNATIONAL EDITION
Copyright © 2021 by Elsevier, Inc. All rights reserved.

ISBN: 978-0-323-53113-9
ISBN: 978-0-323-60992-0

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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This book and the individual contributions contained in it are protected under copyright by the Publisher
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Notice
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Publisher: Jeremy Bowes
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Printed in Canada
Last digit is the print number: 9

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7 6

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2 1

DEDICATION
To
Our teachers
For inspiring us
To
Our students
For constantly challenging us
To our spouses
Raminder Kumar
Ann Abbas
Erin Malone
For their unconditional support

Contributors

Mahul B. Amin, MD

Karen M. Frank, MD, PhD, D(ABMM)

Douglas C. Anthony, MD, PhD

Ryan M. Gill, MD, PhD

Chairman
Department of Pathology
College of Medicine
University of Tennessee Health Science Center
Memphis, Tennessee
The Lower Urinary Tract and Male Genital System
Professor
Pathology, Laboratory Medicine, and Neurology
Warren Alpert Medical School of Brown University;
Chief of Pathology
Lifespan Academic Medical Center
Providence, Rhode Island
Peripheral Nerves and Skeletal Muscles

Anthony Chang, MD

Professor
Department of Pathology
The University of Chicago
Chicago, Illinois
The Kidney

Nicole A. Cipriani, MD

Professor of Pathology
University of California San Francisco School of
Medicine
San Francisco, California
Liver and Gallbladder

Marc K. Halushka, MD, PhD
Deputy Director of Education
Department of Pathology
Professor of Pathology
The Johns Hopkins Hospital
Baltimore, Maryland
Blood Vessels

Andrew Horvai, MD, PhD

Associate Professor of Pathology
The University of Chicago
Chicago, Illinois
Head and Neck

Professor
Department of Pathology
University of California San Francisco
San Francisco, California
Bones, Joints, and Soft Tissue Tumors

Andrew J. Connolly, MD, PhD

Aliya N. Husain, MBBS

Professor of Pathology
University of California San Francisco
San Francisco, California
The Heart

Lora Hedrick Ellenson, MD

Professor
Department of Pathology
The University of Chicago
Chicago, Illinois
Diseases of Infancy and Childhood; The Lung

Attending Physician and Director of Gynecologic
Pathology
Department of Pathology
Memorial Sloan Kettering Cancer Center
New York, New York
The Female Genital Tract

Sanjay Kakar, MD

Robert Folberg, MD

Selene C. Koo, MD, PhD

Departments of Ophthalmology and Pathology
Beaumont Health - Royal Oak
Royal Oak, Michigan
The Eye

vi

Chief
Department of Laboratory Medicine
Clinical Center
National Institutes of Health
Bethesda, Maryland
Infectious Diseases

Professor of Pathology
University of California San Francisco School of
Medicine
San Francisco, California
Liver and Gallbladder
Assistant Professor
Department of Pathology
The Ohio State University;
Pathologist
Department of Pathology and Laboratory Medicine
Nationwide Children’s Hospital
Columbus, Ohio
Diseases of Infancy and Childhood

Contributors

Zoltan G. Laszik, MD, PhD

Professor of Pathology
University of California San Francisco
San Francisco, California
The Kidney

Alexander J. Lazar, MD, PhD

Professor
Departments of Pathology, Genomic Medicine,
Dermatology, and Translational Molecular
Pathology
The University of Texas MD Anderson Cancer Center
Houston, Texas
The Skin

Susan C. Lester, MD, PhD

Assistant Professor
Breast Pathology Services
Department of Pathology
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
The Breast

Mark W. Lingen, DDS, PhD, FRCPath
Professor of Pathology
The University of Chicago
Chicago, Illinois
Head and Neck

Anirban Maitra, MBBS

Professor
Pathology and Translational Molecular Pathology
The University of Texas MD Anderson Cancer Center
Houston, Texas
The Pancreas; The Endocrine System

Marta Margeta, MD, PhD

Associate Professor of Pathology
University of California San Francisco School of
Medicine
San Francisco, California
The Central Nervous System

Alexander J. McAdam, MD, PhD
Associate Professor of Pathology
Department of Pathology
Harvard Medical School;
Medical Director
Clinical Microbiology Laboratory
Boston Children’s Hospital
Boston, Massachusetts
Infectious Diseases

Richard N. Mitchell, MD, PhD

Lawrence J. Henderson Professor of Pathology
Member of the Harvard/MIT Health Sciences and
Technology Faculty
Department of Pathology
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
The Cell as a Unit of Health and Disease; Blood Vessels;
The Heart

George Jabboure Netto, MD

Chair, Department of Pathology
University of Alabama at Birmingham School of
Medicine
Birmingham, Alabama
The Lower Urinary Tract and Male Genital System

Scott A. Oakes, MD

Professor and Vice Chair of Research and Academic
Affairs
Department of Pathology
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Cell Injury, Cell Death, and Adaptations

Arie Perry, MD

Professor of Pathology and Neurological Surgery
Director of Neuropathology
University of California San Francisco
San Francisco, California
The Central Nervous System

Edyta C. Pirog, MD

Associate Professor
Department of Pathology and Laboratory Medicine
Weill Cornell Medicine-New York Presbyterian
Hospital
New York, New York
The Female Genital Tract

Peter Pytel, MD

Professor
Department of Pathology
University of Chicago
Chicago, Illinois
Peripheral Nerves and Skeletal Muscles

vii

Preface

As we launch the tenth edition of Pathologic Basis of Disease
we look to the future of pathology as a discipline and how
this textbook can remain most useful to readers in the
twenty-first century. It is obvious that an understanding
of disease mechanisms is based more than ever on a strong
foundation of basic science. We have always woven the
relevant basic cell and molecular biology into the sections
on pathophysiology in various chapters. In the previous
edition we went one step further and introduced a new
chapter at the very beginning of the book titled “The Cell
as a Unit of Health and Disease.” We are delighted that the
chapter was found useful by many students and faculty.
Because progress in basic cell biology is moving at a very
brisk pace, the chapter has been updated significantly.
In the preface of the very first edition (1957), Stanley
Robbins wrote:
“The pathologist is interested not only in the recognition
of structural alterations, but also in their significance, i.e.,
the effects of these changes on cellular and tissue function and
ultimately the effect of these changes on the patient. It is
not a discipline isolated from the living patient, but rather
a basic approach to a better understanding of disease and therefore
a foundation of sound clinical medicine.”
We hope we continue to illustrate the principles of
pathology that Dr. Robbins enunciated with such elegance
and clarity over half a century ago.
This edition, like all previous ones, has been extensively
revised, and some areas have been completely rewritten.
A few examples of significant changes are as follows:
• Chapter 2 has been updated to include novel pathways
of cell death beyond the long-established pathways of
necrosis and apoptosis. Indeed, the distinction between
these two is being blurred. Autophagy, which has begun
to take center stage in diseases ranging from aging to
cancer and neurodegeneration, has been revised, as have
the possible molecular mechanisms of aging.
• In Chapter 3, we have married morphology with molecular
mechanisms. Thus, different patterns of inflammation
can be related to distinct molecular pathways.
• Chapter 5 includes a discussion of gene editing technology
and a revised and updated section on molecular diagnosis.
• Chapter 7 has been extensively revised to incorporate new
insights into cancer pathogenesis, the interplay between
cancer cells and host immunity, and cancer precision
diagnostics.
• Chapter 10, covering pediatric diseases, includes discussion of newly approved therapies targeting specific
mutated forms of the CFTR transporter.
• Chapter 11, covering vascular diseases, includes discussion
of clonal hematopoiesis, a newly emerging risk factor
for atherosclerosis and other inflammatory disorders.

viii

• Chapters 18 and 28, covering diseases of the liver and
the central nervous system, have a fresh look brought
in by new contributors.
• In addition to the revision and reorganization of the text,
many new photographs and schematics have been added
and a large number of the older “gems” have been
enhanced by digital technology.
We made the changes highlighted above while remaining
focused on the same longstanding overarching goals, which
serve as our guiding principles:
• To integrate into the discussion of pathologic processes
and disorders the newest established information available—morphologic as well as molecular.
• To organize information into logical and uniform presentations, facilitating readability, comprehension, and
learning.
• To maintain the book at a reasonable size and yet provide
adequate discussion of significant lesions, processes, and
disorders. Indeed, despite the addition of new information,
we are happy to state that the overall length of the book
is unchanged. One of our most challenging tasks is to
decide what to eliminate to make room for key new
findings.
• To place great emphasis on clarity of writing and proper
use of language in the recognition that struggling to
comprehend is time-consuming and wearisome and gets
in the way of the learning process.
• To make this text useful to students throughout all of their
years in medical school and into their residencies—but,
at the same time, to provide sufficient detail and depth
to meet the needs of more advanced readers.
We have repeatedly been told by readers that up-todatedness is a special feature that makes this book very
valuable. We have strived to remain current by providing new information from the recent literature, up to the
current year, and by adding coverage of the COVID-19
epidemic.
We are now into the digital age, and so the text will be
available online to those who own the print version. Such
access gives the reader the ability to search across the entire
text, bookmark passages, add personal notes, use PubMed
to view references, and exploit many other exciting features.
In addition, also available online are case studies developed
by one of us (VK), and revised by Dr. Alex Gallan from the
University of Chicago. The cases are designed to enhance
and reinforce learning by challenging students to apply
their knowledge to solve clinical cases. To assist in the
classroom, we have also made the images available for
instructors on the Evolve website. Instructors may register

Preface
at https://evolve.elsevier.com/ to gain access to the images
for teaching purposes.
All three of us have reviewed, critiqued, and edited each
chapter to ensure the uniformity of style and flow that have
been the hallmarks of the book. Together, we hope that we
have succeeded in equipping the readers with the scientific
basis for the practice of medicine and in whetting their

appetite for learning beyond what can be offered in any
textbook.
Vinay Kumar
Abul K. Abbas
Jon C. Aster

ix

Acknowledgments

First and foremost, all four of us offer thanks to our contributing authors for their commitment to this textbook.
Many are veterans of previous editions; others are new
to the tenth edition. All are acknowledged in the table
of contents. Their names lend authority to this book, for
which we are grateful. As in previous editions, the four of
us have chosen not to add our own names to the chapters
we have been responsible for writing, in part or whole. We
welcome to this edition Dr. Jerry Turner in the capacity of
Associate Editor. Jerry is a veteran of Robbins texts having
written the chapter on diseases of the gastrointestinal tract
in previous editions. His editing has strengthened several
chapters.
Many colleagues have enhanced the text by reading
various chapters and providing helpful critiques in their
area of expertise. They include Dr. Celeste Thomas, University of Chicago; Dr. Meenakshi Jolly, Rush University,
Chicago; Dr. Richard Aster, Blood Research Institute,
Milwaukee; and Dr. Suneil Koliwad, UCSF. Many colleagues
provided photographic gems from their collections. They
are individually acknowledged in the text.
All of the graphic art in this book was created by
Mr. James Perkins, Distinguished Professor of Medical
Illustration at Rochester Institute of Technology. His
ability to convert complex ideas into simple and aesthetically pleasing sketches has considerably enhanced this
book.

x

Many individuals associated with our publisher, Elsevier,
need our special thanks. Outstanding among them is Kristine
Feeherty, Health Content Management Specialist, and our
partner in the production of this book. Her understanding
of the needs of the authors, promptness in responding to
requests (both reasonable and unreasonable), and cheerful
demeanor went a long way in reducing our stress and making
our lives less complicated. Jim Merritt handed over the
charge to Jeremy Bowes, Publisher. Our thanks also go to
Director of Content Development, Rebecca Gruliow, and
Designer Brian Salisbury. Undoubtedly there are many others
who may have been left out unwittingly—to them we say
“thank you” and tender apologies for not acknowledging
you individually. We also want to acknowledge many
readers—students, residents, and faculty members—scattered
around the globe whose comments improve the book. We
are impressed by their careful reading of the text.
Efforts of this magnitude take a toll on the families of
the authors. We thank our spouses, Raminder Kumar, Ann
Abbas, Erin Malone, and Judy Turner, for their patience,
love, and support of this venture, and for their tolerance of
our absences.
Vinay Kumar
Abul K. Abbas
Jon C. Aster
Jerrold R. Turner

Contents

CHAPTER 1

The Cell as a Unit of Health and Disease

1

Richard N. Mitchell

CHAPTER 2

Cell Injury, Cell Death, and Adaptations

33

Scott A. Oakes

CHAPTER 3

Inflammation and Repair

71

CHAPTER 4

Hemodynamic Disorders, Thromboembolic Disease, and Shock

115

CHAPTER 5

Genetic Disorders

141

CHAPTER 6

Diseases of the Immune System

189

CHAPTER 7

Neoplasia

267

CHAPTER 8

Infectious Diseases

339

Karen M. Frank • Alexander J. McAdam

CHAPTER 9
CHAPTER 10

Environmental and Nutritional Diseases

405

Diseases of Infancy and Childhood

453

Aliya N. Husain • Selene C. Koo

CHAPTER 11

Blood Vessels

485

Richard N. Mitchell • Marc K. Halushka

CHAPTER 12

The Heart

527

Richard N. Mitchell • Andrew J. Connolly

CHAPTER 13

Diseases of White Blood Cells, Lymph Nodes, Spleen,
and Thymus

583

CHAPTER 14

Red Blood Cell and Bleeding Disorders

635

CHAPTER 15

The Lung

673

Aliya N. Husain

CHAPTER 16

Head and Neck

731

Mark W. Lingen • Nicole A. Cipriani

CHAPTER 17

The Gastrointestinal Tract

753
xi

xii

Contents

CHAPTER 18

Liver and Gallbladder

823

Ryan M. Gill • Sanjay Kakar

CHAPTER 19

The Pancreas

881

Anirban Maitra

CHAPTER 20

The Kidney

895

Anthony Chang • Zoltan G. Laszik

CHAPTER 21

The Lower Urinary Tract and Male Genital System

953

George Jabboure Netto • Mahul B. Amin

CHAPTER 22

The Female Genital Tract

985

Lora Hedrick Ellenson • Edyta C. Pirog

CHAPTER 23

The Breast

1037

Susan C. Lester

CHAPTER 24

The Endocrine System

1065

Anirban Maitra

CHAPTER 25

The Skin

1133

Alexander J. Lazar

CHAPTER 26

Bones, Joints, and Soft Tissue Tumors

1171

Andrew Horvai

CHAPTER 27

Peripheral Nerves and Skeletal Muscles

1217

Peter Pytel • Douglas C. Anthony

CHAPTER 28

The Central Nervous System

1241

Marta Margeta • Arie Perry

CHAPTER 29

The Eye
Robert Folberg

1305

See TARGETED THERAPY available online at www.studentconsult.com

The Cell as a Unit of Health
and Disease

C H A P T E R

1

Richard N. Mitchell
CHAPTER CONTENTS
The Genome 1
Noncoding DNA 1
Histone Organization 3
Micro-RNA and Long Noncoding RNA 4
Micro-RNA 4
Long Noncoding RNA 5

Gene Editing 6

Cellular Housekeeping 6
Plasma Membrane: Protection and
Nutrient Acquisition 8
Membrane Transport 9

Cytoskeleton 11
Cell-Cell Interactions 12
Biosynthetic Machinery: Endoplasmic
Reticulum and Golgi 13
Waste Disposal: Lysosomes and
Proteasomes 14

Cellular Metabolism and
Mitochondrial Function 15
Cellular Activation 16

Modular Signaling Proteins, Hubs, and
Nodes 19
Transcription Factors 19

Growth Factors and Receptors 20
Extracellular Matrix 21
Maintaining Cell Populations 25

Cell Signaling 17
Signal Transduction Pathways 17

Pathology literally translates as the study of suffering (Greek
pathos = suffering, logos = study); more prosaically, and as
applied to modern medicine, it is the study of disease. Virchow
was prescient in asserting that disease originates at the
cellular level, but we now appreciate that cellular pathologies
arise from perturbations in molecules (genes, proteins, and
metabolites) that influence cell survival and behaviors. Thus
the foundation of modern pathology is understanding the
cellular and molecular aberrations that give rise to diseases.
It is illuminating to consider these abnormalities in the
context of normal cellular structure and function, which is
the subject of this introductory chapter.
It is unrealistic (and even undesirable) to condense the
vast and fascinating field of cell biology into a single chapter.
Consequently, rather than attempting a comprehensive
review, the goal here is to survey basic principles and
highlight recent advances that are relevant to the mechanisms
of disease that are emphasized throughout the rest of the
book.

THE GENOME
The sequencing of the human genome at the beginning of
the 21st century represented a landmark achievement of
biomedical science. Since then the rapidly declining cost
of sequencing, the burgeoning computational capacity to
mine the ensuing data, and the expanding toolkits to analyze
functional outputs (genomics, proteomics, and metabolomics)
promise to revolutionize our understanding of health and
disease. The emerging information has also revealed a

Components of the Extracellular
Matrix 23

Proliferation and the Cell Cycle 25
Stem Cells 28
Regenerative Medicine 29

breathtaking level of complexity far beyond the linear
sequence of the genome. The potential of these powerful
innovations to explain disease pathogenesis and drive
therapeutic discovery excites and inspires scientists and the
lay public alike.

Noncoding DNA
The human genome contains some 3.2 billion DNA
base pairs. Yet, within the genome there are only about
20,000 protein-encoding genes, constituting just 1.5%
of the genome. These are the blueprints that instruct the
assembly of the enzymes, structural elements, and signaling
molecules within the 50 trillion cells that make up the human
body. Although 20,000 underestimates the actual number
of encoded proteins (many genes produce multiple RNA
transcripts that translate to different protein isoforms), it
is nevertheless startling to realize that worms, which are
composed of fewer than 1000 cells and have 30-fold smaller
genomes also have about 20,000 protein-encoding genes.
Many of these proteins are recognizable homologs of
molecules expressed in humans. What then separates humans
from worms?
The answer is not completely known, but evidence
suggests that much of the difference lies in the 98.5% of
the human genome that does not encode proteins. The
function of such long stretches of DNA (so-called genome
“dark matter”) was mysterious for many years. However,
over 85% of the human genome is ultimately transcribed;
nearly 80% is devoted to regulation of gene expression. It
follows that while proteins provide the building blocks and

1

2

CHAPTER 1

The Cell as a Unit of Health and Disease

machinery required for assembling cells, tissues, and organisms, it is the noncoding regions of the genome that provide
the critical “architectural planning.” Practically stated, the
difference between worms and humans apparently lies
more in the genomic “blueprints” than in the construction
materials.
There are five major classes of functional non–proteincoding sequences in the human genome (Fig. 1.1):
• Promoter and enhancer regions that provide binding sites
for transcription factors.
• Binding sites for factors that organize and maintain higher
order chromatin structures.
• Noncoding regulatory RNAs. Over 60% of the genome
is transcribed into RNAs that are never translated
but regulate gene expression through a variety of mechanisms. The two best-studied varieties—micro-RNAs
(miRNAs) and long noncoding RNAs (lncRNAs)—are
described later.
• Mobile genetic elements (e.g., transposons) make up more
than a third of the human genome. These “jumping genes”
can move around the genome during evolution, resulting
in variable copy number and positioning even among
closely related species (e.g., humans and other primates).
Although implicated in gene regulation and chromatin
organization, the function of mobile genetic elements is
not well established.

Heterochromatin

Nucleolus

Euchromatin

Nucleus

• Special structural regions of DNA, in particular, telomeres
(chromosome ends) and centromeres (chromosome
“tethers”). A major component of centromeres is so-called
satellite DNA, consisting of large arrays—up to megabases
in length—of repeating sequences (from 5 bp up to 5 kb).
Although classically associated with spindle apparatus
attachment, satellite DNA is also important in maintaining
the dense, tightly packed organization of heterochromatin
(discussed later).
Many genetic variations (polymorphisms) associated with
diseases are located in non–protein-coding regions of the
genome. Thus variation in gene regulation may prove to
be more important in disease causation than structural
changes in specific proteins. Another surprise that emerged
from genome sequencing is that any two humans are typically
more than 99.5% DNA-identical (and are 99% sequenceidentical with chimpanzees)! Thus individual variation,
including differential susceptibility to diseases and environmental stimuli, is encoded in less than 0.5% of our DNA
(representing about 15 million bp).
The two most common forms of DNA variation in the
human genome are single nucleotide polymorphisms
(SNPs) and copy number variations (CNVs).
• SNPs are variants at single nucleotide positions and are
almost always biallelic (only two choices exist at a given

Heterochromatin
(dense, inactive)

Euchromatin
(disperse, active)

Nucleosome
DNA

Transcription
PremRNA

Cell

p arm

Promoter

Exon

mRNA
5’ UTR

Centromere
Chromosome

Enhancer

Intron Splicing Intron

q arm

Telomeres

Exon

Open-reading frame

Exon

Intron

3’ UTR

Translation
Protein

Figure 1.1 The organization of nuclear DNA. At the light microscopic level, the nuclear genetic material is organized into dispersed, transcriptionally
active euchromatin and densely packed, transcriptionally inactive heterochromatin; chromatin can also be mechanically connected with the nuclear
membrane, and membrane perturbation can thus influence transcription. Chromosomes (as shown) can be visualized only during mitosis. During mitosis,
they are organized into paired chromatids connected at centromeres; the centromeres act as the locus for the formation of a kinetochore protein
complex that regulates chromosome segregation at metaphase. The telomeres are repetitive nucleotide sequences that cap the termini of chromatids and
permit repeated chromosomal replication without deterioration of genes near the ends. The chromatids are organized into short “P” (“petite”) and long
“Q” (next letter in the alphabet) arms. The characteristic banding pattern of chromatids has been attributed to relative GC content (less GC content in
bands relative to interbands), with genes tending to localize to interband regions. Individual chromatin fibers are comprised of a string of nucleosomes—
DNA wound around octameric histone cores—with the nucleosomes connected via DNA linkers. Promoters are noncoding regions of DNA that initiate
gene transcription; they are on the same strand and upstream of their associated gene. Enhancers can modulate gene expression over distances of 100 kb
or more by looping back onto promoters and recruiting additional factors that drive the expression of pre–messenger RNA (mRNA) species. Intronic
sequences are spliced out of the pre-mRNA to produce the final message that is translated into protein—without the 3′–untranslated region (UTR) and
5′-UTR. In addition to the enhancer, promoter, and UTR sequences, noncoding elements, including short repeats, regulatory factor binding regions,
noncoding regulatory RNAs, and transposons, are distributed throughout the genome.

The genome
site within the population, such as A or T). Over 6 million
human SNPs have been identified, with many showing
wide variation in frequency in different populations.
• SNPs occur across the genome—within exons, introns,
intergenic regions, and coding regions.
• Roughly 1% of SNPs occur in coding regions, which
is about what would be expected by chance, since
coding regions comprise about 1.5% of the genome.
• SNPs located in noncoding regions can occur within
genomic regulatory elements, thereby altering gene
expression; in such instances, SNPs influence disease
susceptibility directly.
• Some SNPs, termed “neutral” variants, are thought
to have no effect on gene function or individual
phenotype.
• Even “neutral” SNPs may be useful markers if they
happen to be coinherited with a disease-associated
polymorphism as a result of physical proximity. In
other words, the SNP and the causative genetic factor
are in linkage disequilibrium.
• The effect of most SNPs on disease susceptibility is
weak, and it remains to be seen if identification of
such variants, alone or in combination, can be used
to develop effective strategies to identify those at risk
and, ultimately, prevent disease.
• CNVs are a form of genetic variation consisting of different
numbers of large contiguous stretches of DNA; these
can range from 1000 base pairs to millions of base pairs.
CNVs can be biallelic and simply duplicated or, alternatively, deleted in some individuals. At other sites there
are complex rearrangements of genomic material, with
multiple variants in the human population.
• CNVs are responsible for between 5 million and 24
million base pairs of sequence difference between any
two individuals.
• Approximately 50% of CNVs involve gene-coding
sequences; thus CNVs may underlie a large portion
of human phenotypic diversity.
It is important to note that alterations in DNA sequence
cannot by themselves explain the diversity of phenotypes
in human populations; moreover, classic genetic inheritance
cannot explain differing phenotypes in monozygotic twins.
The answers to these conundrums probably lie in epigenetics—
heritable changes in gene expression that are not caused
by variations in DNA sequence (see the following section).

•

•

•

•

Histone Organization
Even though virtually all cells in the body have the same
genetic composition, differentiated cells have distinct
structures and functions that arise as a result of lineagespecific gene expression programs. Such cell type–specific
differences in transcription and translation depend on
epigenetic factors (literally, factors that are “above genetics”)
that can be conceptualized as follows (Fig. 1.2):
• Histones and histone-modifying factors. Nucleosomes consist
of DNA segments 147 bp long that are wrapped around
a central core structure of highly conserved low molecular
weight proteins called histones. The resulting DNA-histone
complex resembles a series of beads joined by short DNA
linkers. The naked DNA of a single human cell is about
1.8 m long. By winding around histones, like spools of

•

thread, the entire genome can be packed into a nucleus
as small as 7 to 8 µm in diameter. In most cases, this
structured DNA, termed chromatin, is not wound uniformly. Thus at the light microscopic level, nuclear
chromatin is recognizable as cytochemically dense and
transcriptionally inactive heterochromatin and disperse,
transcriptionally active euchromatin (see Fig. 1.1). In
general, only the regions that are “unwound” are available
for transcription. Chromatin structure can therefore regulate transcription independent of traditional promoters
and DNA-binding elements and, due to variations between
cell types, helps to define cellular identity and activity.
Histones are not static, but rather are highly dynamic
structures regulated by a host of nuclear proteins.
Thus chromatin remodeling complexes can reposition
nucleosomes on DNA, exposing (or obscuring) gene
regulatory elements such as promoters. “Chromatin
writer” complexes, on the other hand, carry out over 70
different histone modifications generically denoted as
“marks.” Such covalent alterations include methylation,
acetylation, or phosphorylation of specific amino acids
within histones.
Actively transcribed genes in euchromatin are associated with histone marks that make the DNA accessible
to RNA polymerases. In contrast, inactive genes have
histone marks that enable DNA compaction into heterochromatin. Histone marks are reversible through the
activity of “chromatin erasers.” Still other proteins
function as “chromatin readers,” binding histones that
bear particular marks and thereby regulating gene
expression.
Histone methylation. Both lysines and arginines can be
methylated by specific writer enzymes; methylation of
histone lysine residues can lead to transcriptional activation or repression, depending on which histone residue
is marked.
Histone acetylation. Lysine residues are acetylated by
histone acetyltransferases (HATs), whose modifications
tend to open the chromatin and increase transcription.
In turn, these changes can be reversed by histone deacetylases (HDACs), leading to chromatin condensation.
Histone phosphorylation. Serine residues can be modified
by phosphorylation; depending on the specific residue,
the DNA may be opened for transcription or condensed
and inactive.
DNA methylation. High levels of DNA methylation in
gene regulatory elements typically result in transcriptional
silencing. Like histone modifications, DNA methylation
is tightly regulated by methyltransferases, demethylating
enzymes, and methylated-DNA-binding proteins.
Chromatin organizing factors. Much less is known about
these proteins, which are believed to bind to noncoding
regions and control long-range looping of DNA, thus
regulating the spatial relationships between enhancers
and promoters that control gene expression.

Deciphering the mechanisms that allow epigenetic factors
to control genomic organization and gene expression in a
cell-type-specific fashion is an extraordinarily complex
proposition. Despite the intricacies, there is already ample
evidence that dysregulation of the “epigenome” has a central
role in malignancy (Chapter 7), and emerging data indicate

3

CHAPTER 1

The Cell as a Unit of Health and Disease

A
Core DNA
(1.8 turns)

DNA

H2A

Nucleosome

4

H4

Histone
protein
core

H2B
H3
Linker
DNA
H1
Linker DNA

B

Heterochromatin
(inactive)

Linker
histone H1

Euchromatin
(active)
Methylation
Acetylation

H1

H1

H1

H1

Figure 1.2 Histone organization. (A) Nucleosomes are comprised of octamers of histone proteins (two each of histone subunits H2A, H2B, H3, and H4)
encircled by 1.8 147 bp DNA loops. Histones sit on 20- to 80-nucleotide stretches of linker DNA between nucleosomes. Histone subunits are positively
charged, thus allowing compaction of negatively charged DNA. (B) The relative state of DNA unwinding (and thus access for transcription factors) is
regulated by histone modification, including acetylation, methylation, and/or phosphorylation; these “marks” are dynamically written and erased. Certain
marks such as histone acetylation “open up” the chromatin structure, whereas others such as methylation of particular histone residues condense DNA
to silence genes. DNA can also be methylated, leading to transcriptional inactivation.

that many other diseases are associated with inherited or
acquired epigenetic alterations. Unlike genetic changes, many
epigenetic alterations (e.g., histone acetylation and DNA
methylation) are reversible and amenable to therapeutic
intervention; HDAC and DNA methylation inhibitors are
already being tested in the treatment of various forms of
cancer.

Micro-RNA and Long Noncoding RNA
Genes can also be regulated by noncoding RNAs. These
genomic sequences are transcribed but not translated.
Although many distinct families of noncoding RNAs exist,
we will discuss only two examples here: small RNA molecules
called microRNAs (miRNAs) and long noncoding RNAs
(lncRNAs) (>200 nucleotides in length).

Micro-RNA
miRNAs do not encode proteins; they modulate translation
of target messenger RNAs (mRNAs). Posttranscriptional
silencing of gene expression by miRNA is a fundamental
and well-conserved mechanism of gene regulation present
in all eukaryotes (plants, animals, and fungi). Even bacteria

have a primitive version of the same machinery that they
use to protect themselves against foreign DNA (e.g., phage
and virus DNA). The profound influence of miRNAs on
protein expression allows these relatively short RNAs (22
nucleotides on average) to be critical regulators of developmental pathways as well as pathologic conditions (e.g.,
cancer).
The human genome encodes almost 6000 miRNA genes,
about 30% of the total number of protein-coding genes.
Individual miRNAs can regulate multiple protein-coding
genes, allowing each miRNA to coregulate entire programs
of gene expression. Transcription of miRNA genes produces
a primary transcript (pri-miRNA) that is processed into
progressively smaller segments, including trimming by the
enzyme Dicer. This generates mature single-stranded
miRNAs of 21 to 30 nucleotides that associate with a
multiprotein aggregate called RNA-induced silencing complex
(RISC) (Fig. 1.3). Subsequent base pairing between the
miRNA strand and its target mRNA directs the RISC to
either induce mRNA cleavage or repress its translation. In
this way the target mRNA is posttranscriptionally silenced.
Small interfering RNAs (siRNAs) are short RNA sequences
that can be introduced experimentally into cells where they

The genome
serve as substrates for Dicer and interact with RISC, thereby
reproducing endogenous miRNAs function. Synthetic siRNAs
that target specific mRNA species are powerful laboratory
tools to study gene function (so-called knockdown technology) and are also being studied as potential therapeutic
agents to silence pathogenic genes (e.g., oncogenes that drive
neoplastic transformation).

miRNA gene

pri-miRNA

Long Noncoding RNA
Target gene

pre-miRNA
Export
protein

pre-miRNA

Dicer

Recent studies have further identified an untapped universe
of lncRNAs—by some calculations, the number of lncRNAs
may exceed coding mRNAs by 10-fold to 20-fold. lncRNAs
modulate gene expression by several mechanisms (Fig. 1.4).
As one example, lncRNAs can bind to chromatin and restrict
RNA polymerase from accessing coding genes within that
region. The best-known example is XIST, which is transcribed
from the X chromosome and plays an essential role in the
physiologic X chromosome inactivation that occurs in

A. Gene activation
lncRNA

Target mRNA

Ribonucleoprotein
transcription complex
Gene activation

miRNA
Unwinding of
miRNA duplex
RISC
complex

B. Gene suppression

Imperfect
match

Decoy lncRNA

Gene suppression

Perfect
match
Target
mRNA

Translational
repression

mRNA
cleavage

C. Promote chromatin modification
Methylation,
acetylation

Ribosome
GENE SILENCING
Figure 1.3 Generation of microRNAs (miRNAs) and their mode of
action in regulating gene function. Transcription of a miRNA produces a
primary miRNA (pri-miRNA), which is processed within the nucleus to
form pre-miRNA composed of a single RNA strand with secondary hairpin
loop structures and stretches of double-stranded RNA. After export out
of the nucleus via specific transporter proteins, pre-miRNA is trimmed by
the cytoplasmic Dicer enzyme to generate mature double-stranded
miRNAs of 21 to 30 nucleotides. The miRNA subsequently unwinds and
the single strands are incorporated into multiprotein RNA-induced
silencing complexes (RISC). Base pairing between single-stranded miRNA
and the targeted messenger RNA (mRNA) directs RISC to either cleave
or repress translation of the mRNA, resulting in posttranscriptiontional
silencing.

D. Assembly of protein complexes
Act on chromatin
structure

Multi-subunit complex
Figure 1.4 Roles of long noncoding RNAs (lncRNAs). (A) lncRNAs can
facilitate transcription factor binding and thus promote gene activation.
(B) Conversely, lncRNAs can preemptively bind transcription factors to
inhibit transcription. (C) Histone and DNA modification by acetylases or
methylases (or deacetylases and demethylases) may be directed by
lncRNA binding. (D) In other instances, lncRNAs can act as scaffolds to
stabilize secondary or tertiary structures and multisubunit complexes that
influence chromatin architecture or gene activity. (Modified from Wang
KC, Chang HY: Molecular mechanisms of long noncoding RNAs, Mol Cell
43:904, 2011.)

5

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CHAPTER 1

The Cell as a Unit of Health and Disease

females. XIST itself escapes X inactivation but forms a
repressive “cloak” on the X chromosome from which it is
transcribed, resulting in gene silencing. Conversely, many
enhancers are actually sites of lncRNA synthesis. In this
case the lncRNAs expand transcription from gene promoters
via a variety of mechanisms (see Fig. 1.4).

Homologous gRNA sequence
Cas9
protein

gRNA

Gene Editing
An exciting new development that allows high-fidelity
genome editing may usher in the next era of the molecular
revolution. This advance comes from a wholly unexpected
source: the discovery of clustered regularly interspaced short
palindromic repeats (CRISPRs) and CRISPR-associated genes
(Cas), such as the Cas9 nuclease. These are linked genetic
elements that endow prokaryotes with a form of acquired
immunity to phages and plasmids. Bacteria use the system
to sample the DNA of infecting agents and integrate portions
into their genomes as CRISPRs. These CRISPR segments
are subsequently transcribed and processed into guide RNA
sequences that bind and direct the Cas9 nuclease to specific
sites (e.g., a phage sequence) so that it can be cleaved to
disable the infecting agent.
Gene editing repurposes this process by using artificial
20-base guide RNAs (gRNAs) that bind Cas9 and are
complementary to a targeted DNA sequence (Fig. 1.5). Cas9
then induces double-stranded DNA breaks at the site of
gRNA binding. Repair of the highly specific cleavages can
lead to random disruptive mutations (through nonhomologous end joining) or can introduce new genetic material
with precision (by homologous recombination). Both the
guide sequences and the Cas enzyme, either as a coding
DNA (cDNA) or a protein, can be easily introduced into
cells. The potential application to genetic engineering, due
to the impressive specificity of the Cas9 system (up to
10,000-fold better than other previous editing systems), has
led to great excitement. Applications include inserting specific
mutations in cells and tissues to model cancers and other
diseases and rapidly generating transgenic animal models
from edited embryonic stem cells. CRISPR also makes it
possible to selectively edit mutations that cause hereditable
disease, or—perhaps more worrisome—to just eliminate
less “desirable” traits. Predictably the technology has inspired
a vigorous debate regarding the ethics of its use.

CELLULAR HOUSEKEEPING
Normal functioning and intracellular homeostasis depend
on a variety of fundamental cell housekeeping functions that
all differentiated cells must perform to maintain viability
and normal activity. These include protection from the
environment, nutrient acquisition, metabolism, communication, movement, renewal of senescent molecules, molecular
catabolism, and energy generation.
Many of the normal housekeeping functions of the cell
are compartmentalized within membrane bound intracellular organelles (Fig. 1.6). By isolating certain cellular
functions within distinct compartments, potentially injurious
degradative enzymes or toxic metabolites can be kept at
usefully high concentrations without risking damage to
more delicate intracellular constituents. Moreover,

Cleavage
Double-stranded
DNA
Target genomic
sequence
Double-stranded DNA break

NHEJ
HDR

Insertion/
deletion

Donor DNA

DNA with random mutation

DNA with specific mutation

Figure 1.5 Gene editing with clustered regularly interspersed short
palindromic repeats (CRISPRs) and the nuclease Cas9. In bacteria, DNA
sequences consisting of CRISPRs are transcribed into guide RNAs (gRNAs)
with a constant region and a variable sequence of approximately 20 bases.
The gRNA constant regions bind to Cas9, while the variable regions form
heteroduplexes with homologous DNA sequences of interest; the Cas9
nuclease then cleaves the bound DNA to produce a double-stranded
DNA break. In nature, bacteria use the CRISPR/Cas9 system to protect
against phages and plasmids; CRISPR sequences from previous assaults are
transcribed into gRNA from the bacterial genome. These bind to pathogen
nucleotide sequences and form a complex with the Cas9 nuclease that
leads to cleavage and, ultimately, destruction of the invader’s DNA.
To perform gene editing, gRNAs are designed with variable regions that
are homologous to a specific DNA sequence of interest; coexpression of
the gRNA and Cas9 then leads to efficient and highly specific cleavage of
the target sequence. In the absence of homologous DNA, the doublestranded break is repaired by nonhomologous end-joining (NHEJ), an
error-prone mechanism that typically introduces disruptive insertions or
deletions (indels). Conversely, in the presence of homologous “donor”
DNA that spans the region target by the CRISPR/Cas9 complex, cells
instead can use homologous DNA recombination (HDR) to repair the
break. HDR is less efficient than NHEJ but has the capacity to introduce
precise changes in DNA sequence. Potential applications of CRISPR/Cas9
coupled with HDR include repair of inherited genetic diseases and the
creation of pathogenic mutations in inducible pluripotent stem cells.

compartmentalization also allows the creation of unique
intracellular environments (e.g., low pH or high calcium)
that permit more efficient functioning of certain enzymes
or metabolic pathways.
New proteins destined for the plasma membrane or
secretion are physically assembled in the rough endoplasmic

Cellular housekeeping
Relative volumes of intracellular organelles (hepatocyte)
Compartment
Cytosol
Mitochondria
Rough ER
Smooth ER, Golgi
Nucleus
Endosomes
Lysosomes
Peroxisomes

% total volume
54%
22%
9%
6%
6%
1%
1%
1%

Golgi
apparatus

number/cell
1
1700
1
1
1
200
300
400

role in the cell
metabolism, transport, protein translation
energy generation, apoptosis
synthesis of membrane and export protein
protein modification, sorting, catabolism
cell regulation, proliferation, DNA transcription
intracellular transport and export
cellular catabolism
very long-chain fatty acid metabolism

Rough
Free
endoplasmic
ribosomes
reticulum

Nucleolus
Nucleus

Lysosome
Mitochondrion

Endosome

Cytoskeleton
Plasma
membrane

Peroxisome
Microtubules

Smooth
endoplasmic
reticulum

Centrioles

Figure 1.6 Basic subcellular constituents of cells. The table presents the number of the various organelles within a typical hepatocyte, as well as their
volume within the cell. The figure shows geographic relationships but is not intended to be accurate to scale. ER, Endoplasmic reticulum. (Modified from
Weibel ER, Stäubli W, Gnägi HR, et al: Correlated morphometric and biochemical studies on the liver cell. I. Morphometric model, stereologic methods, and
normal morphometric data for rat liver. J Cell Biol 42:68, 1969.)

reticulum (RER) and Golgi apparatus; proteins intended for the
cytosol are synthesized on free ribosomes. Smooth endoplasmic
reticulum (SER) is used for steroid hormone and lipoprotein
synthesis and modification of hydrophobic compounds into
water-soluble molecules for export.
Cells catabolize the wide variety of molecules that they
endocytose, as well as the entire repertoire of their own
proteins and organelles—all of which are constantly being
degraded and renewed. Breakdown of these constituents
takes place at three different sites, ultimately serving different
functions.
• Proteasomes are “disposal” complexes that degrade
denatured or otherwise “tagged” cytosolic proteins. In
antigen-presenting cells, the resulting short peptides
are presented in the context of class I or class II major
histocompatibility molecules to help drive the adaptive
immune response (Chapter 6). In other cases, proteasomal

degradation of regulatory proteins or transcription factors
can trigger initiation or suppression of signaling pathways.
• Lysosomes are intracellular organelles containing degradative enzymes that permit digestion of a wide range of
macromolecules, including proteins, polysaccharides,
lipids, and nucleic acids. They are the site of senescent
intracellular organelle breakdown (a process called
autophagy) and where phagocytosed microbes are killed
and catabolized.
• Peroxisomes contain catalase, peroxidase, and other oxidative enzymes; they play a specialized role in the breakdown of very long-chain fatty acids, generating hydrogen
peroxide in the process.
The contents and location of cellular organelles are also
highly regulated. Endosomal vesicles shuttle internalized
material to the appropriate intracellular site(s), while other

7

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CHAPTER 1

The Cell as a Unit of Health and Disease

membrane-bound vesicles direct newly synthesized materials
to the cell surface or specific organelles. Movement—of both
organelles and proteins within the cell, as well as the entire
cell in its environment—is accomplished by the cytoskeleton,
which is composed of filamentous actin (microfilaments),
keratins (intermediate filaments), and microtubules. These
structural proteins also maintain cellular shape and intracellular organization, which are essential to generation and
maintenance of cell polarity. This is particularly important
in epithelium where the top of the cell (apical) and the bottom
and sides of the cell (basolateral) are exposed to different
environments and have distinct functions. Loss of polarity
could, for example, disrupt vectorial transcellular transport
in the intestine or renal tubule.
Cell growth and maintenance require a constant supply
of both energy and the building blocks that are needed for
synthesis of macromolecules. Most of the adenosine triphosphate (ATP) that powers cells is generated via mitochondrial oxidative phosphorylation. Mitochondria also serve
as an important source of metabolic intermediates needed
for anabolic metabolism, are sites of synthesis of certain
macromolecules (e.g., heme), and contain important sensors
of cell damage that can initiate and regulate programmed
cell death (e.g., apoptosis).
In growing and dividing cells, all of these organelles
have to be replicated (organellar biogenesis) and correctly
apportioned in daughter cells following mitosis. Moreover, because the macromolecules and organelles have
finite lifespans (mitochondria, for example, last only

Plasma Membrane: Protection and
Nutrient Acquisition
Plasma membranes (and all other organellar membranes for
that matter) are more than just static lipid sheaths. Rather,
they are fluid bilayers of amphipathic phospholipids—
hydrophilic head groups that face the aqueous environment
and hydrophobic lipid tails that interact with each other
to form a barrier to passive diffusion of large or charged
molecules (Fig. 1.7). The bilayer has a remarkably heterogeneous composition of different phospholipids that vary by
location and are also asymmetric—that is, membrane lipids
preferentially associate with extracellular or cytosolic faces.
Proper localization of these molecules is important for cell
health. For example, specific phospholipids interact with
particular membrane proteins and modify their distributions
and functions.
• Phosphatidylinositol on the inner membrane leaflet can be
phosphorylated, serving as an electrostatic scaffold for
intracellular proteins; alternatively, polyphosphoinositides
can be hydrolyzed by phospholipase C to generate
intracellular second signals like diacylglycerol and inositol
trisphosphate.

Extracellular
protein

Outside
Phosphatidylcholine
(outer mostly)

about 10 days), mechanisms must also exist that allow for
the recognition and degradation of “worn-out” cellular
components.
With this as a primer, we will now move on to discuss
cellular components and their function in greater detail.

Glycosylphosphatidylinositol
(GPI) linked protein

Glycolipids
Sphingomyelin
(outer mostly)

Lipid
raft

P

P

Phosphatidylethanolamine
(inner mostly)

Phosphatidylserine
(inner mostly)

Phosphatidyl- Cholesterol
inositol
(both faces)
(both faces)
Transmembrane proteins

Cytoplasm

A

B

Lipid-linked protein

Cytosolic
protein

Figure 1.7 Plasma membrane organization and asymmetry. (A) The plasma membrane is a bilayer of phospholipids, cholesterol, and associated proteins.
The phospholipid distribution within the membrane is asymmetric due to the activity of flippases; phosphatidylcholine and sphingomyelin are
overrepresented in the outer leaflet, and phosphatidylserine (negative charge) and phosphatidylethanolamine are predominantly found on the inner leaflet;
glycolipids occur only on the outer face where they contribute to the extracellular glycocalyx. Although the membrane is laterally fluid and the various
constituents can diffuse randomly, specific domains, for example cholesterol and glycosphingolipid-rich lipid rafts, can also form. (B) Membrane-associated
proteins may traverse the membrane (singly or multiply) via α-helical hydrophobic amino acid sequences; depending on the membrane lipid content and
relative hydrophobicity of protein domains, such proteins may have nonrandom distributions within the membrane. Proteins on the cytosolic face can be
associated with the plasma membrane through posttranslational modifications (e.g., farnesylation) or addition of palmitic acid. Proteins on the
extracytoplasmic face can associate with the membrane via glycosylphosphatidylinositol (GPI) linkages. Besides protein-protein interactions within the
membrane, membrane proteins can also associate with extracellular and/or intracytoplasmic proteins to generate distinct domains (e.g., the focal adhesion
complex). Transmembrane proteins can translate mechanical forces (e.g., from the cytoskeleton or extracellular matrix), as well as chemical signals across
the membrane.

Cellular housekeeping
• Phosphatidylserine is normally restricted to the inner face
where it confers a negative charge involved in electrostatic
protein interactions; however, when flipped to the
extracellular leaflet, it becomes a potent “eat me” signal
during programmed cell death (e.g., apoptosis). In
platelets, phosphatidylserine is also a cofactor in blood
clotting.
• Glycolipids and sphingomyelin are preferentially located
on the extracellular face; glycolipids, including gangliosides with complex sugar linkages and terminal sialic
acids that confer negative charges, support charge-based
interactions that contribute to including inflammatory
cell recruitment and sperm-egg fusion.

composition. The latter strategy is used to maintain cell
polarity (e.g., top/apical/free vs. bottom/basolateral/
bound to extracellular matrix [ECM]) in epithelial cells.
Interactions of other membrane and cytosolic proteins with
one another and the cytoskeleton also contributes to cell
polarity.
The extracellular face of the plasma membrane is diffusely decorated by carbohydrates, not only as complex
oligosaccharides on glycoproteins and glycolipids, but also
as polysaccharide chains attached to integral membrane
proteoglycans. This glycocalyx can form a chemical and
mechanical barrier.

Despite substantial lateral fluidity, some membrane
constituents concentrate into specialized domains (e.g., lipid
rafts) that are enriched in glycosphingolipids and cholesterol.
Since inserted membrane proteins have different intrinsic
solubilities in domains with distinct lipid compositions, this
membrane organization also impacts protein distribution.
This geographic organization of plasma membrane components impacts cell-cell and cell-matrix interactions, intracellular signaling, and the specialized sites of vesicle budding
or fusion.
The plasma membrane is liberally studded with a
variety of proteins and glycoproteins involved in (1) ion
and metabolite transport; (2) fluid-phase and receptormediated uptake of macromolecules; and (3) cell-ligand,
cell-matrix, and cell-cell interactions. The means by which
these proteins associate with membranes frequently reflects
function. For example, multiple transmembrane-spanning
proteins are often pores or molecular transporters, while
proteins that are superficially attached to the membrane via
labile linkages are more likely to participate in signaling.
In general, proteins associate with the lipid bilayer by one
of four mechanisms.
• Most proteins are integral or transmembrane proteins,
having one or more relatively hydrophobic α-helical
segments that traverse the lipid bilayer.
• Proteins synthesized on free ribosomes in the cytosol
may be modified posttranslationally by addition of prenyl
groups (e.g., farnesyl, related to cholesterol) or fatty acids
(e.g., palmitic or myristic acid) that insert into the cytosolic
side of the plasma membrane.
• Proteins on the extracellular face of the membrane may
be anchored by glycosylphosphatidylinositol (GPI) tails
that are added posttranslationally.
• Peripheral membrane proteins may noncovalently associate with true transmembrane proteins.

Although the barrier provided by plasma membranes is
critical, transport of selected molecules across the lipid bilayer
or to intracellular sites via vesicular transport is essential.
Several mechanisms contribute to this transport.

Many plasma membrane proteins function as large
complexes; these may be aggregated either under the control
of chaperone molecules in the RER or by lateral diffusion
in the plasma membrane, followed by complex formation
in situ. For example, many protein receptors (e.g., cytokine
receptors) dimerize or trimerize in the presence of ligand
to form functional signaling units. Although lipid bilayers
are fluid within the plane of the membrane, components
can be confined to discrete domains. This can occur by
localization to lipid rafts (discussed earlier) or through
intercellular protein-protein interactions (e.g., tight junctions)
that establish discrete boundaries and also have unique lipid

Membrane Transport

Passive Diffusion. Small, nonpolar molecules like O2 and
CO2 readily dissolve in lipid bilayers and therefore rapidly
diffuse across them. Larger hydrophobic molecules, (e.g.,
steroid-based molecules like estradiol or vitamin D) can
also cross lipid bilayers with relative impunity. While
small polar molecules such as water (18 Da) can also diffuse
across membranes at low rates, in tissues responsible for
significant water movement (e.g., renal tubular epithelium),
special integral membrane proteins called aquaporins form
transmembrane channels for water, H2O2, and other small
molecules. In contrast, the lipid bilayer is an effective barrier
to the passage of larger polar molecules (>75 Da); at 180 Da,
for example, glucose is effectively excluded. Lipid bilayers are also impermeant to ions due to their charge and
hydration.
Carriers and Channels (Fig. 1.8). Plasma membrane

transport proteins are required for uptake and secretion of
ions and larger molecules that are required for cellular
function (e.g., nutrient uptake and waste disposal). Ions
and small molecules can be transported by channel proteins
and carrier proteins. Similar pores and channels also mediate
transport across organellar membranes. These transporters
that move ions, sugars, nucleotides, etc., frequently have
exquisite specificities, and can be either active or passive
(see below). For example, some transporters accommodate
glucose but reject galactose.
• Channel proteins create hydrophilic pores, which, when
open, permit rapid movement of solutes (usually restricted
by size and charge).
• Carrier proteins bind their specific solute and undergo a
series of conformational changes to transfer the ligand
across the membrane; their transport is relatively slow.
Solute transport across the plasma membrane is frequently
driven by a concentration and/or electrical gradient between
the inside and outside of the cell via passive transport (virtually
all plasma membranes have an electrical potential difference
across them, with the inside negative relative to the outside).
In other cases, active transport of certain solutes (against a
concentration gradient) is accomplished by carrier molecules
(never channels) at the expense of ATP hydrolysis or a
coupled ion gradient. For example, most apical nutrient

9

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CHAPTER 1
Extracellular

Carrier

Energy
Membrane

The Cell as a Unit of Health and Disease
Channel

Endocytosis

Exocytosis

Coated
pit
Caveolin

Coated
vesicle

Early
endosome
(low pH)

Transcytosis

Microbe

Caveolae- Receptors Receptormediated
mediated

Cytosol

Phagocytosis

Receptor
recycling
Lysosome
Phagosome

Reconstitution
Phagolysosome

Late
endosome

Lysosome-late
endosome
fusion vesicle

Undigested
residual material

Figure 1.8 Movement of small molecules and larger structures across membranes. The lipid bilayer is relatively impermeable to all but the smallest and/or
most hydrophobic molecules. Thus the import or export of charged species requires specific transmembrane transporter proteins, vesicular traffic, or
membrane deformations.
From left to right in the figure: Small charged solutes can move across the membrane using either channels or carriers; in general, each molecule
requires a unique transporter. Channels are used when concentration gradients can drive the solute movement; activation of the channel opens a
hydrophilic pore that allows size-restricted and charge-restricted flow. Carriers are required when solute is moved against a concentration gradient; this
typically requires energy expenditure to drive a conformational change in the carrier that facilitates the transmembrane delivery of specific molecules.
Receptor-mediated and fluid-phase uptake of material involves membrane bound vesicles. Caveolae endocytose extracellular fluid, membrane proteins,
and some receptor bound molecules (e.g., folate) in a process driven by caveolin proteins concentrated within lipid rafts. They can subsequently fuse with
endosomes or recycle to the membrane. Endocytosis of receptor-ligand pairs often involves clathrin-coated pits and vesicles. After internalization the
clathrin disassembles and individual components can be re-used. The resulting vesicle becomes part of the endocytic pathway, in which compartments are
progressively more acidic. After ligand is released, the receptor can be recycled to the plasma membrane to repeat the process (e.g., iron dissociates from
transferin at pH ~5.5; apotransferrin and the transferrin receptor then return to the surface). Alternatively, receptor and ligand complexes can eventually
be degraded within lysosomes (e.g., epidermal growth factor and its receptor are both degraded, which prevents excessive signaling). Exocytosis is the
process by which membrane-bound vesicles fuse with the plasma membrane and discharge their contents to the extracellular space. This includes
endosome recycling (shown), release of undigested residual material from lysosomes, transcytotic delivery of vesicles, and export of secretory vacuole
contents (not shown). Phagocytosis involves membrane invagination to engulf large particles and is most common in specialized phagocytes (e.g.,
macrophages and neutrophils). The resulting phagosomes eventually fuse with lysosomes to facilitate the degradation of the internalized material.
Transcytosis can mediate transcellular transport in either apical-to-basal or basal-to-apical directions, depending on the receptor and ligand.

transporters in the intestines and renal tubules exploit the
extracellular to intracellular Na+ gradient to allow absorption
even when intracellular nutrient concentrations exceed
extracellular concentrations. This form of active transport
does not use ATP directly, but depends on the Na+ gradient
generated by Na+-Ka+ ATPase. Other transporters are
ATPases. One example is the multidrug resistance (MDR)
protein, which pumps polar compounds (e.g., chemotherapeutic drugs) out of cells and may render cancer cells resistant
to treatment.
Water movement into or out of cells is passive and
directed by solute concentrations. Thus extracellular salt in
excess of that in the cytoplasm (hypertonicity) causes net
movement of water out of cells, while hypotonicity causes
net movement of water into cells. Conversely, the charged
metabolites and proteins within the cytoplasm attract charged

counterions that increase intracellular osmolarity. Thus to
prevent overhydration, cells must constantly pump out small
inorganic ions (e.g., Na+)—typically through the activity of
the membrane ion-exchanging ATPase. Loss of the ability
to generate energy (e.g., in a cell injured by toxins or
ischemia) therefore results in osmotic swelling and eventual
cell rupture. Similar transport mechanisms also regulate
concentrations of other ions (e.g., Ca2+ and H+). This is critical
to many processes. For example, cytosolic enzymes are most
active at pH 7.4 and are often regulated by Ca2+, whereas
lysosomal enzymes function best at pH 5 or less.
Uptake of fluids or macromolecules by the cell is called
endocytosis. Depending on the size of the vesicle, endocytosis
may be denoted pinocytosis (“cellular drinking”) or phagocytosis (“cellular eating”). Generally, phagocytosis is
restricted to certain cell types (e.g., macrophages and

Cellular housekeeping
neutrophils) whose role is to specifically ingest invading
organisms or dead cell fragments.

Receptor-Mediated and Fluid-Phase Uptake (see Fig. 1.8)
Certain small molecules—including some vitamins—bind
to cell-surface receptors and are taken up through invaginations of the plasma membrane called caveolae. Uptake
can also occur through membrane invaginations coated by
an intracellular matrix of clathrin proteins that spontaneously assemble into a basket-like lattice which helps drive
endocytosis (discussed more later). In both cases, activity
of the “pinchase” dynamin is required for vesicle release.
Macromolecules can also be exported from cells by
exocytosis. In this process, proteins synthesized and packaged
within the RER and Golgi apparatus are concentrated in
secretory vesicles, which then fuse with the plasma membrane to expel their contents. Common examples include
peptide hormones (e.g., insulin) and cytokines.
Transcytosis is the movement of endocytosed vesicles
between the apical and basolateral compartments of cells.
This is a mechanism for transferring large amounts of intact
proteins across epithelial barriers (e.g., ingested antibodies
in maternal milk) or for rapid movement of large solute
volumes.
We now return to the specifics of endocytosis (see Fig. 1.8).
• Caveolae-mediated endocytosis. Caveolae (“little caves”) are
noncoated plasma membrane invaginations associated
with GPI-linked molecules, cyclic adenosine monophosphate (cAMP) binding proteins, src-family kinases, and
the folate receptor; caveolin is the major structural protein
of caveolae, which, like membrane rafts (see above), are
enriched in glycosphingolipids and cholesterol. Internalization of caveolae along with bound molecules and
associated extracellular fluid is called potocytosis—literally
“cellular sipping.” In addition to supporting transmembrane delivery of some molecules (e.g., folate), caveolae
regulate transmembrane signaling and cellular adhesion
via internalization of receptors and integrins.
• Receptor-mediated endocytosis. Macromolecules bound to
membrane receptors (such as transferrin or low-density
lipoprotein [LDL] receptors) are taken up at specialized
regions of the plasma membrane called clathrin-coated
pits. The receptors are efficiently internalized by membrane invaginations driven by the associated clathrin
matrix, eventually pinching off to form clathrin-coated
vesicles. Trapped within these vesicles is also a gulp of
the extracellular milieu (fluid-phase pinocytosis). The vesicles
then rapidly lose their clathrin coating and fuse with an
acidic intracellular structure called the early endosome;
the endosomal vesicles undergo progressive maturation
to late endosomes, ultimately fusing with lysosomes. In
the acidic environment of the endosomes, LDL and
transferrin receptors release their cargo (cholesterol and
iron, respectively), which is then transported into the
cytosol.
After release of bound ligand, some receptors recycle
to the plasma membrane and are reused (e.g., transferrin
and LDL receptors), while others are degraded within
lysosomes (e.g., epidermal growth factor receptor). In
the latter case, degradation after internalization results
in receptor downregulation that limits receptor-mediated

signaling. Defects in receptor-mediated transport of LDL
underlie familial hypercholesterolemia, as described in
Chapter 5.
Endocytosis requires recycling of internalized vesicles
back to the plasma membrane (exocytosis) for another round
of ingestion. This is critical, as a cell will typically ingest
from the extracellular space the equivalent of 10% to 20%
of its own cell volume each hour—amounting to 1% to 2%
of its plasma membrane each minute! Without recycling,
the plasma membrane would be rapidly depleted. Endocytosis and exocytosis must therefore be tightly coupled to
avoid large changes in plasma membrane area.

Cytoskeleton
The ability of cells to adopt a particular shape, maintain
polarity, organize intracellular organelles, and migrate
depends on an intracellular scaffold of structural proteins
that form the cytoskeleton (Fig. 1.9). Although the cytoskeleton can have an appearance similar to the beams and
supports of a building, cytoskeletal structures are constantly
elongating and shrinking; microfilaments and microtubules
are most active, and their assembly and disassembly can
drive cell migration.
In eukaryotic cells, there are three major classes of
cytoskeletal proteins.
• Actin microfilaments are 5- to 9-nm diameter fibrils formed
from the globular protein actin (G-actin), the most

Microvilli

Microtubules
Tight junction
Actin
microfilaments
Adherins
junction
Desmosome
Gap junctions

Intermediate
filaments
Hemidesmosome
Basement membrane

Integrins

Figure 1.9 Cytoskeletal elements and cell-cell interactions. Interepithelial
adhesion involves several different surface protein interactions at tight
junctions, adherens junctions, and desmosomes; adhesion to the
extracellular matrix involves cellular integrins (and associated proteins)
within hemidesmosomes. The various adhesion proteins within the plasma
membrane associate with actin microfilaments and intermediate filaments
to provide a mechanical matrix for cell structure and signaling. Gap
junctions do not impart structural integrity but allow cell-cell
communication by the movement of small molecular weight and/or
charged species. See text for details.

11

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CHAPTER 1

The Cell as a Unit of Health and Disease

abundant cytosolic protein in cells. G-actin monomers
noncovalently polymerize into long filaments (F-actin)
that intertwine to form double-stranded helices with a
defined polarity. Although the details are (as always)
more nuanced, new subunits are typically added at
the “positive” end of the strand and removed from the
“negative” end—a process referred to as actin treadmilling. Actin nucleating, binding, and regulatory proteins
organize polymerization, bundling, and branching to
form networks that control cell shape and movement.
This complex and its association with motor proteins
(e.g., myosin) is so precisely arrayed in skeletal and
cardiac muscle that a banding pattern is apparent by
light microscopy. ATP hydrolysis by myosin slides the
actin filaments relative to one another to cause muscle
contraction. Although less coordinated, myosins, of which
there are many, are responsible for other functions that
depend on actin contraction including vesicular transport,
epithelial barrier regulation, and cell migration.
• Intermediate filaments are 10-nm diameter fibrils that
comprise a large and heterogeneous family that includes
keratin proteins and nuclear lamins. Intermediate filaments predominantly form ropelike polymers and do not
usually actively reorganize like actin and microtubules.
This allows intermediate filaments to provide tensile
strength so that cells can bear mechanical stress, e.g., in
epithelia where intermediate filaments link desmosomes
and hemidesmosomes (see Fig. 1.9). Individual intermediate filament proteins have characteristic tissue-specific
patterns of expression that can be useful for assigning a
cell of origin for poorly differentiated tumors. Examples
include:
• Vimentin, in mesenchymal cells (fibroblasts,
endothelium).
• Desmin in muscle cells forms the scaffold on which
actin and myosin contract.
• Neurofilaments are critical for neuronal axon structure
and confer both strength and rigidity.
• Glial fibrillary acidic protein is expressed in glial cells.
• Cytokeratins are expressed in epithelial cells. There are
at least 30 distinct different cytokeratins that are
expressed in different cell lineages (e.g., lung vs.
gastrointestinal epithelium).
• Lamins are intermediate filament proteins that form
the nuclear lamina, define nuclear shape, and can
regulate transcription.
• Microtubules are 25-nm-thick fibrils composed of noncovalently polymerized α- and β-tubulin dimers organized
into hollow tubes. These fibrils are extremely dynamic
and polarized, with “+” and “−” ends. The “−” end is
typically embedded in a microtubule organizing center
(MTOC or centrosome) near the nucleus, where it is associated with paired centrioles; the “+” end elongates or
recedes in response to various stimuli by the addition
or subtraction of tubulin dimers. Microtubules:
• Serve as mooring lines for molecular motor proteins
that use ATP to translocate vesicles, organelles, or
other molecules around cells. There are two varieties
of these motor proteins, kinesins and dyneins, that
typically (but not exclusively) transport cargo in
anterograde (− to +) or retrograde (+ to −) directions,
respectively.

• Mediate sister chromatid segregation during mitosis.
• Form the core of primary cilia, single nonmotile projections on many nucleated cells that contribute to the
regulation of cellular proliferation and differentiation (mutations in the proteins of the primary cilia
complex lead to forms of polycystic kidney disease; see
Chapter 20).
• Can be adapted to form the core of motile cilia (e.g.,
in bronchial epithelium) or flagella (in sperm).

Cell-Cell Interactions
Cells connect and communicate with each other via
junctional complexes that form mechanical links and
facilitate receptor-ligand interactions. Similar complexes
also mediate interaction with the ECM. Cell-cell junctions
are organized into three basic types (see Fig. 1.9):
• Occluding junctions (tight junctions) seal adjacent epithelial
cells together to create a continuous barrier that restricts
the paracellular (between cells) movement of ions and
other molecules. Occluding junctions form a tight meshlike
network (when viewed en face by freeze-fracture electron
microscopy) of macromolecular contacts between neighboring cells; the complexes that mediate the cell-cell
interactions are composed of transmembrane proteins
including the tetraspanning claudin and tight junction–
associated MARVEL protein (TAMP) families. These connect
to a host of intracellular adaptor and scaffolding proteins,
including the three members of the zonula occludens protein
family (ZO-1, ZO-2, ZO-3) and cingulin. Besides forming
a selectively permeable barrier that seals the space
between cells (i.e., the paracellular space), this zone also
represents the boundary that separates apical and basolateral membrane domains and helps to maintain cellular
polarity. Nevertheless, these junctions are dynamic
structures that can be modified to facilitate epithelial
healing and inflammatory cell migration across epitheliallined mucosal surfaces.
• Anchoring junctions (adherens junctions and desmosomes)
mechanically attach cells—and their cytoskeletons—to
other cells or the ECM. Adherens junctions are often closely
associated with and beneath tight junctions. Desmosomes
are more basal and form several types of junctions. When
desmosomes attach the cell to the extracellular matrix
(ECM) they are referred to as hemidesmosomes (half a
desmosome), since the other half of the desmosome is
not present within the ECM. Both adherens junctions
and desmosomes are formed by homotypic extracellular
interactions between transmembrane glycoproteins called
cadherins, on adjacent cells.
• In adherens junctions the transmembrane adhesion
molecules are associated with intracellular actin
microfilaments through which they can also influence
cell shape and/or motility. Loss of the epithelial
adherens junction protein E-cadherin explains the
discohesive invasion pattern of some gastric cancers
and lobular carcinomas of the breast (Chapters 17
and 23).
• In desmosomes the cadherins are linked to intracellular
intermediate filaments, allowing extracellular forces
to be mechanically communicated (and dissipated)
over multiple cells.

Cellular housekeeping
• In hemidesmosomes the transmembrane connector
proteins are called integrins; like desmosomal cadherins,
these attach to intermediate filaments and link the
cytoskeleton to the ECM. Focal adhesion complexes are
composed of >100 proteins and localize at hemidesmosomes. Their component proteins can generate
intracellular signals when cells are subjected to shear
stress (e.g., endothelium in the bloodstream or cardiac
myocytes in a failing heart).
• Communicating junctions (gap junctions) permit the diffusion
of chemical or electrical signals from one cell to another.
The junction consists of a dense planar array of 1.5- to
2-nm pores (called connexons) formed by a pair of hexamers (one on each cell) of transmembrane connexin proteins.
These form pores that permit passage of ions, nucleotides,
sugars, amino acids, vitamins, and other small molecules;
permeability of the junction is rapidly reduced by lowered
intracellular pH or increased intracellular calcium. Gap
junctions play a critical role in cell-cell communication.
For example, gap junctions in cardiac myocytes allow
cell-to-cell calcium fluxes that allow the many cells of
the myocardium to behave as a functional syncytium
with coordinated waves of contraction.

Biosynthetic Machinery: Endoplasmic Reticulum
and Golgi Apparatus
All cellular constituents—including structural proteins,
enzymes, transcription factors, and even the phospholipid
membranes—are constantly renewed in an ongoing process
balancing synthesis and degradation. The endoplasmic
reticulum (ER) is the site for synthesis of all transmembrane
proteins and lipids for plasma membrane and cellular
organelles, including the ER itself. It is also the initial site
of synthesis for secreted proteins. The ER is organized into
a meshlike interconnected maze of branching tubes and
flattened lamellae, forming a continuous sheet around a
single lumen that is topologically equivalent to the extracellular environment. ER is composed of contiguous but distinct
domains that are distinguished by the presence (RER) or
absence (SER) of ribosomes (see Fig. 1.6).
• Rough endoplasmic reticulum (RER): Membrane-bound
ribosomes on the cytosolic face of RER translate mRNA
into proteins that are extruded into the ER lumen or become
integrated into the ER membrane. This process is directed
by specific signal sequences on the N-termini of nascent
proteins; synthesis of proteins with signal peptides is
initiated on free ribosomes, but the complex then becomes
attached to the ER membrane, and the protein is inserted
into or passed across the ER membrane as it is translated.
For proteins lacking a signal sequence, translation remains
on free ribosomes in the cytosol, forming polyribosomes
as multiple ribosomes attach to the mRNA; such transcribed
proteins remain within the cytoplasm.
Proteins inserted into the ER fold into their active
conformation and can form polypeptide complexes
(oligomerize); in addition, disulfide bonds are formed,
and N-linked oligosaccharides (sugar moieties attached
to asparagine residues) are added. Chaperone molecules
assist in folding and retaining proteins in the ER until
the modifications are complete and the proper conformation is achieved. If a protein fails to appropriately fold

or oligomerize, it is retained and degraded within the
ER. A good example of this is the most common mutation
of the CFTR protein in cystic fibrosis. In mutant CFTR,
a codon deletion leads to the absence of a single amino
acid (Phe508) which results in its misfolding, ER retention
and catabolism and therefore reduced surface expression.
Moreover, excess accumulation of misfolded proteins—
exceeding the capacity of the ER to edit and degrade
them—leads to the ER stress response (also called the
unfolded protein response [UPR]) (Fig. 1.10B). Detection of
excess abnormally folded proteins leads to a reduction
in protein synthesis overall with a concurrent increase
in chaperone proteins; failure to correct the overload can
trigger cell death through apoptosis (Chapter 2).
• Golgi apparatus: From the RER, proteins and lipids
destined for other organelles or extracellular export are
shuttled into the Golgi apparatus. This consists of stacked
cisternae that progressively modify proteins in an orderly
fashion from cis (near the ER) to trans (near the plasma
membrane). Cisternal progression, i.e., movement of
cis-face cisternae to the trans aspect of the Golgi, akin
to steps on an escalator, allows sequential processing of
newly synthesized proteins and can be facilitated by small
membrane-bound vesicles. Similar vesicles shuttle Golgiresident enzymes from trans to cis in order to maintain the
different cisternal contents along this assembly line. As
cisternae mature, the N-linked oligosaccharides originally
added in the ER are pruned and extended in a stepwise
fashion; O-linked oligosaccharides (sugar moieties
linked to serine or threonine) are also appended. Some
of this glycosylation is important in sorting molecules
to lysosomes (via the mannose-6-phosphate receptor);
other glycosylation adducts are important for cell-cell
or cell-matrix interactions or for clearing senescent
cells (e.g., platelets and erythrocytes). In the trans Golgi
network, proteins and lipids are sorted and dispatched
to other organelles, plasma membrane, or secretory
vesicles. The Golgi complex is especially prominent in
cells specialized for secretion, including goblet cells of
the intestinal or bronchial epithelium, which secrete large
amounts of polysaccharide-rich mucus. In plasma cells
that secrete antibodies, the Golgi can be recognized as a
perinuclear hoff on simple hematoxylin and eosin stains
(Chapter 6).
• Smooth endoplasmic reticulum (SER): In most cells, the SER is
relatively sparse and primarily exists as the transition zone
extending from RER to generate transport vesicles that
carry newly synthesized proteins to the Golgi apparatus.
The SER may, however, be particularly conspicuous
in cells that synthesize steroid hormones (e.g., within
the gonads or adrenals) or that catabolize lipid-soluble
molecules (e.g., hepatocytes). Indeed, repeated exposure
to compounds that are metabolized by the SER (e.g.,
phenobarbital, which is catabolized by the cytochrome
P-450 system) can lead to SER hyperplasia. The SER is
also responsible for sequestering intracellular calcium,
which, when released into the cytosol, can mediate a
number of responses to extracellular signals (including
apoptotic cell death). In muscle cells, specialized SER
called sarcoplasmic reticulum is responsible for the cyclic
release and sequestration of calcium ions that regulate
muscle contraction and relaxation, respectively.

13

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CHAPTER 1
A

The Cell as a Unit of Health and Disease

LYSOSOMAL DEGRADATION
Endoplasmic
reticulum

Nucleus
Endocytosis
Endosome

Senescent
organs

Phagocytosis

Denatured proteins
Lysosomes
LC3
Phagosome
AUTOPHAGY

HETEROPHAGY
Autophagosome

Phagolysosome

Exocytosis

B

PROTEASOMAL DEGRADATION

CYTOSOL

Nascent
peptide
chains

Chaperones

Age, UV, heat,
reactive oxygen
species
Folded
Senescent or
protein
denatured
protein

Multiple
ubiquitins
E1, E2, E3
ligases
Proteasome

Peptide
fragments

Free ubiquitin
Metabolic alterations (e.g., pH)
Genetic mutations
Viral infections

ENDOPLASMIC RETICULUM

“ER stress”
(unfolded protein
response)
Excess
misfolded
protein

APOPTOSIS

Protein synthesis
Chaperone production

Figure 1.10 Intracellular catabolism. (A) Lysosomal degradation. In heterophagy (right side of panel A), lysosomes fuse with endosomes or phagosomes to
facilitate the degradation of their internalized contents (see Fig. 1.8). The end products may be released into the cytosol for nutrition or discharged into
the extracellular space (exocytosis). In autophagy (left side of panel A), senescent organelles or denatured proteins are targeted for lysosome-driven
degradation as they are encircled within a double membrane vacuole derived from the endoplasmic reticulum and marked by LC3 protein (microtubuleassociated protein 1A/1B-light chain 3). Cell stress, such as nutrient depletion or some intracellular infections, can also activate the autophagocytic pathway.
(B) Proteosomal degradation. Cytosolic proteins destined for turnover (e.g., transcription factors or regulatory proteins), senescent proteins, or proteins
that have become denatured due to extrinsic mechanical or chemical stresses can be tagged by multiple ubiquitin molecules (through the activity of E1, E2,
and E3 ubiquitin ligases). This marks the proteins for degradation by proteasomes, cytosolic multi-subunit complexes that degrade proteins to small peptide
fragments. High levels of misfolded proteins within the endoplasmic reticulum (ER) trigger a protective unfolded protein response—engendering a broad
reduction in protein synthesis, but specific increases in chaperone proteins that can facilitate protein refolding. If this is inadequate to cope with
the levels of misfolded proteins it can lead to apoptosis.

Waste Disposal: Lysosomes and Proteasomes
Although cells rely primarily on lysosomes to digest internalized material and accumulated internal waste, there are
multiple other routes to degrade intracellular macromolecules
(see Fig. 1.10). These include proteosomes and peroxisomes.

The latter are responsible for catabolism of long-chained
fatty acids.
• Lysosomes are membrane-bound organelles containing
roughly 40 different acid hydrolases (i.e., that function
best at pH ≤5); these include proteases, nucleases, lipases,
glycosidases, phosphatases, and sulfatases. Lysosomal

Cellular metabolism and mitochondrial function
enzymes are initially synthesized in the ER lumen and
then tagged with mannose-6-phosphate (M6P) within
the Golgi apparatus. These M6P-modified proteins are
subsequently delivered to lysosomes through trans Golgi
vesicles that express M6P receptors. The other macromolecules destined for catabolism in the lysosomes arrive
by one of three pathways (see Fig. 1.10).
• Material internalized by fluid-phase or receptor-mediated
endocytosis passes from plasma membrane to early
and then late endosomes and ultimately arrives at the
lysosome. These compartments are progressively
acidified such that proteolytic enzymes become active
in late endosome and lysosomes.
• Senescent organelles and/or large, denatured protein
complexes can be ferried into lysosomes by a process
called autophagy (Chapter 2). Through a mechanism
involving the products of a number of autophagyrelated (Atg) genes, obsolete organelles are corralled
by a double membrane derived from the ER. The membrane progressively expands to encircle a collection
of organelles and cytosolic constituents, forming the
definitive autophagosome; these structures are targeted
for eventual destruction by fusion with lysosomes. In
addition to facilitating turnover of aged and/or defunct
structures, autophagy can be used to preserve viability
during nutrient depletion; is involved in protective
responses to intracellular infections; participates in
intracellular repair; and, under some circumstances,
triggers programmed cell death (apoptosis). Autophagy
is discussed in more detail in Chapter 2.
• Phagocytosis of microorganisms or large fragments of
matrix or debris occurs primarily in professional
phagocytes (macrophages or neutrophils). The material
is engulfed to form a phagosome that subsequently fuses
with lysosomes.
• Proteasomes play an important role in degrading cytosolic
proteins (see Fig. 1.10); these include denatured or
misfolded proteins as well as any other macromolecule
whose lifespan needs to be regulated (e.g., signaling
molecules). Many proteins destined for destruction are
identified by covalently binding a small protein called
ubiquitin. Polyubiquitinated molecules are unfolded and
funneled into the polymeric proteasome complex—a
cylinder containing multiple protease activities, each with
its active site pointed at the hollow core. Proteasomes
digest proteins into small (6 to 12 amino acids) fragments
that can subsequently be degraded to their constituent
amino acids and recycled.

CELLULAR METABOLISM AND
MITOCHONDRIAL FUNCTION
Mitochondria evolved from ancestral prokaryotes that were
engulfed by primitive eukaryotes about 1.5 billion years ago.
Their origin explains why mitochondria contain their own
DNA that encodes about 1% of total cellular protein and
approximately 20% of the proteins involved in oxidative phosphorylation. Although their genomes are small, mitochondria
can carry out all the steps of DNA replication, transcription, and
translation using machinery similar to present-day bacteria;

for example, mitochondria initiate protein synthesis with
N-formylmethionine and are sensitive to some antibacterial
antibiotics. Since mitochondria biogenesis requires a genetic
contribution from preexisting mitochondria and the ovum
contributes the vast majority of cytoplasmic organelles in
the fertilized zygote, mitochondrial DNA is almost entirely
maternally inherited. Nevertheless, because the protein
constituents of mitochondria are encoded by both nuclear
and mitochondrial DNA, mitochondrial disorders may be
X-linked, autosomal, or maternally inherited.
Mitochondria are impressively dynamic, constantly
undergoing fission and fusion with other newly synthesized
mitochondria; this supports their renewal and defends
against degenerative changes that occur through ongoing
oxygen free radical damage. Even so, mitochondria are
short-lived—being degraded through autophagy (a process
called mitophagy)—with estimated half-lives of 1 to 10 days,
depending on the tissue, nutritional status, metabolic
demands, and intercurrent injury.
Besides providing the enzymatic machinery for oxidative
phosphorylation (and thus the relatively efficient generation
of energy from glucose and fatty acid substrates), mitochondria play a fundamental role in regulating apoptosis
(Fig. 1.11). Details of mitochondrial functions follow:
• Energy generation. Each mitochondrion has two separate
membranes with distinct functions; the inner membrane
contains the enzymes of the respiratory chain folded into
cristae. This encloses a core matrix space that harbors
the bulk of the enzymes of the glycolytic and tricarboxylic
acid cycles, and these constitute the major working parts
of the organelle. Outside the inner membrane is the
intermembrane space, which is the site of nucleotide
phosphorylation and is, in turn, enclosed by the outer
membrane; the latter is studded with porin proteins that
form voltage-dependent anion channels that are permeable
to small (<5000 Da) molecules. As with other cellular
membranes, larger molecules (and even some smaller
polar species) require specific transporters.
The major source of the energy that facilitates all
cellular functions derives from oxidative metabolism.
Mitochondria oxidize substrates to CO2, transferring the
high-energy electrons from the original molecule (e.g.,
sugar) to molecular oxygen. Oxidation of various metabolites drives proton pumps that transfer H+ from the core
matrix into the intermembrane space. As the H+ ions
flow down their electrochemical gradient and out of the
intermembrane space, the energy released is used to
generate ATP.
Notably, the electron transport chain need not necessarily be coupled to ATP generation. An inner membrane
protein enriched in brown fat called thermogenin (also
called uncoupling protein-1 [UCP-1]) is a hydrogen ion
transporter that can dissipate the proton gradient,
uncoupling it from oxidative phosphorylation. By this
means, there is rapid substrate oxidation without ATP
synthesis that allows tissues with high levels of UCP-1
to generate heat (nonshivering thermogenesis). As a
natural (albeit usually low-level) by-product of substrate
oxidation and electron transport, mitochondria are also
an important source of reactive oxygen species (oxygen
free radicals, hydrogen peroxide, etc.); importantly,
hypoxia, toxic injury, or even mitochondrial aging can

15

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CHAPTER 1

The Cell as a Unit of Health and Disease

METABOLITES
(glucose, glutamine,
fatty acids)
Intermembrane space
(ATP generation)

TCA cycle
intermediates

Lipid, amino acid and protein, and
nucleic acid building blocks
ATP GENERATION

Inner membrane
(respiratory chain
proteins)

APOPTOSIS SIGNALS

Outer membrane

Bax/Bak complexes

Mitochondrion

Core matrix
(citric acid cycle
enzymes)

H+

H+

Mitochondrial outer membrane
permeabilization (MOMP)
Cytochrome C

Injury

Membrane
permeability
transition pores

Stabilized
apoptosome

H+

ISCHEMIA,
TOXIN

ATP
CELL DEATH
(necrosis)

Caspase cascade
CELL DEATH
(apoptosis)

Figure 1.11 Roles of the mitochondria. Besides the efficient generation of adenosine triphosphate (ATP) from carbohydrate and fatty acid substrates,
mitochondria also play an important role in intermediary metabolism—serving as the source of substrates used to synthesize lipids, proteins, and
nucleotides. Significantly, they are centrally involved in cell life-and-death decisions: (1) toxic or ischemic injury will induce a membrane permeability
transition that dissipates the intermembrane proton gradient, leading to cell death through loss of ATP generation; (2) intracellular signaling from both
intrinsic and extrinsic sources can also result in the formation of oligomerized Bax and Bak protein pores on mitochondrial outer membrane
permeabilization (MOMP) that facilitate release of cytochrome C from the electron transport chain proteins. Cytosolic cytochrome C stabilizes the
multisubunit apoptosome to promote caspase activation and ultimately apoptotic cell death. TCA, Tricarboxylic acid.

lead to oxidative stress, characterized by increases in
intracellular reactive oxygen species.
• Intermediate metabolism. Oxidative phosphorylation efficiently generates 36 to 38 ATP molecules per glucose
molecule, but also “burns” substrates to their core CO2
and H2O, leaving no carbon moieties to use for building
lipids and proteins. Consequently, to ensure the necessary
building blocks for growth, rapidly dividing cells (both
benign and malignant) increase their uptake of glucose
and glutamine and switch to aerobic glycolysis, a phenomenon called the Warburg effect. In that setting, each
glucose molecule is catabolized to lactic acid (even in
the presence of adequate oxygen), generating only two
net ATP molecules but “spinning off” intermediates that
can be converted into new lipids, amino acids and
proteins, and nucleic acids. Thus mitochondrial metabolism can be modulated to support either cellular energy
maintenance or cellular proliferation.
• Cell death. In addition to providing the ATP that enables
the bulk of cellular activity, mitochondria are fundamental
to cell survival. The role of mitochondria in cell death is
detailed in Chapter 2 and briefly mentioned here.
• Necrosis: External cellular injury (toxin, ischemia,
trauma) can damage mitochondria, inducing the
formation of mitochondrial permeability transition
pores in the outer membrane. These channels allow
the dissipation of the proton gradient so that subsequent mitochondrial ATP generation becomes impossible and the cell dies.

• Apoptosis: Programmed cell death is a central feature
of normal tissue development and turnover and can
be triggered by extrinsic signals (including cytotoxic
T cells or inflammatory cytokines) or intrinsic pathways (including DNA damage or intracellular stress).
Mitochondria integrate intracellular proapoptotic and
antiapoptotic effector signals to generate a final “go” or
“no go” signal for apoptosis. A net proapoptotic signal
results in mitochondrial outer membrane permeabilization (MOMP)—distinct from the mitochondrial
permeability transition—that releases cytochrome
C (and other proteins) into the cytoplasm. In turn,
these proteins activate intracellular programmed
cell death pathways. Notably, a failure of normal
proapoptotic signaling (or too many antiapoptotic
effectors) can underlie malignancy—even in the face
of mutations that would otherwise trigger cellular
suicide. Conversely, too strong an apoptotic signal
(or lack of antiapoptotic effectors) may lead to premature cell death, as in neurodegenerative disorders
(Chapter 28).

CELLULAR ACTIVATION
Intercellular communication is essential to multicellular
organisms. At the most basic level, extracellular signals may
determine whether a cell lives or dies, remains quiescent,

Cellular activation
or becomes active to perform its specific functions. Intercellular signaling is critical in the developing embryo and in
maintaining tissue organization; it is also important in adult
organisms, where intercellular signaling assures that all
tissues act in appropriate concert (e.g., in response to local
tissue trauma or a systemic infection). Loss of intercellular
communication and “social controls” can also be reflected
in unregulated growth (e.g., cancer) or in detrimental
responses to extrinsic stress (e.g., shock).

Cell Signaling
Individual cells are chronically exposed to a remarkable
cacophony of signals that must be integrated into rational
output; some signals may induce a given cell type to differentiate, while others signal proliferation or direct the cell
to perform specialized functions. Multiple signals at once,
in a certain ratio, may trigger yet another totally unique
response. Many cells require certain input just to continue
living; in the absence of appropriate exogenous signals, they
die by apoptosis.
The signals that most cells respond to can be classified
into several groups.
• Danger and pathogens. Many cells have an innate capacity
to sense and respond to damaged cells (danger signals),
as well as foreign invaders such as microbes. The involved
receptors are discussed in Chapters 3 and 6.
• Cell-cell contacts, mediated through adhesion molecules
and/or gap junctions. As mentioned previously, gap
junction signaling is accomplished between adjacent cells
via hydrophilic connexon channels that permit the movement of small ions (e.g., calcium), metabolites, and second
messenger molecules (e.g., cAMP).
• Cell-ECM contacts, mediated through integrins. We will
return to a consideration of integrins in the context of
leukocyte attachment to other cells during inflammation
in Chapter 3.
• Secreted molecules. The most important secreted molecules
include growth factors (discussed later); cytokines, a term
reserved for mediators of inflammation and immune
responses (discussed also in Chapters 3 and 6); and
hormones, which are secreted by endocrine organs
(Chapter 24).
Signaling pathways can also be classified based on the
spatial relationships between the sending and receiving
cells.
• Paracrine signaling. Only cells in the immediate vicinity
are affected. To accomplish this, there can be only minimal
diffusion, after which the secreted signal is rapidly
degraded, taken up by other cells, or trapped in the ECM.
• Autocrine signaling occurs when molecules secreted by a
cell affect that same cell. This can be a means to entrain
groups of cells undergoing synchronous differentiation
during development, or it can be used to amplify (positive
feedback) or dampen (negative feedback) a particular
response.
• Synaptic signaling. Activated neurons secrete neurotransmitters at specialized cell junctions (i.e., synapses) onto
target cells.
• Endocrine signaling. A mediator is released into the
bloodstream and acts on target cells at a distance.

Regardless of the nature of an extracellular stimulus
(paracrine, autocrine, synaptic, or endocrine), the signal
that is conveyed is transmitted to the cell via specific
receptor proteins. Signaling molecules (ligands) bind their
respective receptors and initiate a cascade of intracellular
events culminating in the desired cellular response. Ligands
usually have high affinities for their receptors (≤10−8 M)
and, at physiologic concentrations, bind receptors with
exquisite specificity. Receptors may be present on the cell
surface or within the cell (Fig. 1.12).
• Intracellular receptors include transcription factors that
are activated by lipid-soluble ligands that can easily transit
plasma membranes; vitamin D and steroid hormones
that activate nuclear hormone receptors are good
examples. In other cases a small and/or nonpolar signaling
ligand produced by one cell type can influence the activity
of adjacent cells. Thus