Introduction to Molecular Medicine

159 Pages·2002·4.02 MB·English

by  Dennis W. Ross M.D., Ph.D. (auth.)

Introduction to
Molecular Medicine
Third Edition
Dennis W. Ross, M.D., Ph.D.
Department of Pathology
Forsyth Medical Center and
Wake Forest University
School of Medicine
Winston-Salem, North Carolina
Introduction to
Molecular Medicine
Third Edition
Illustrations by David Pounds
With 58 Illustrations
~ Springer
Dennis W. Ross, M.D., Ph.D.
Department of Pathology
Forsyth Medical Center
3333 Silas Creek Parkway
Winston-Salem, NC 27103, USA
and
Clinical Professor, Pathology
Wake Forest University
School of Medicine
Winston-Salem, NC 27103, USA
[email protected]
Library of Congress Cataloging-in-Publication Data
Ross, D.W. (Dennis W.)
Introduction to molecular medicine / Dennis W. Ross.-3rd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-387-95372-4 ISBN 978-0-387-22521-0 (eBook)
DOI 10.1007/978-0-387-22521-0
1. Medical genetics. 2. Molecular biology. 3. Pathology, Molecular. 1. Title.
[DNLM: 1. Genetics, Medical. 2. Hereditary Diseases-genetics. 3. Molecular Biol
ogy. 4. Neoplasms-genetics. QZ 50 R823i 2002]
RB155 .R78 2002
616' .042-dc21 2001054921
Printed on acid-free paper.
© 2002, 1996, 1992 Springer Science+Business Media New York
Originally published by Springer-Verlag New York, Inc. in 2002
All rights reserved. This work may not be translated or copied in whole or in part without the written
permission of the publisher (Springer Science+Business Media, LLC), except for brief excerpts in
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and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now
known or hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks and similar terms, even if they
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9876543
springeronline.com
Preface to the Third Edition
This book continues the story of a new field called molecular medi
cine. The first edition appeared 10 years ago in a previous millennium.
At that time cloning a gene was cutting edge research; now gene
cloning is a high school science fair project. The complete sequencing
of the human genome was finished last year; cloning a human is a
likely (and very controversial) event for 2002. The tools of molecular
medicine have become very powerful and automated; DNA on a chip
and microarrays allow us to probe large parts of the genome and its
function. The speed of sequencing DNA has increased about 100,000-
fold over the decade since the first edition of this book was published.
Following the great improvements in technology, DNA and molecular
research have a rapidly deepening impact on human medicine. Molec
ular therapies including DNA vaccines, antisense, and gene transplan
tation are undergoing clinical trials.
This third edition is almost entirely new. All of the figures and about
90% of the text are new. The message is the same. I present the discov
eries, basic scientific concepts, and sense of excitement that surrounds
what is clearly a revolution in medicine. Do not be put off by technical
detail and jargon; it will all be explained. Concepts in boldface type are
defined in the glossary. Each chapter begins with an overview and ends
with a summary. This book is not a comprehensive monograph; I stick
to the basic concepts as demonstrated by important clinical examples.
The goal is to prepare us for the very great changes that will result from
our decoding and understanding of the human genome and the molec
ular basis of life.
Dennis W Ross, M.D., Ph.D.
Winston-Salem, North Carolina
Preface to the Second Edition
In the four years since the first edition of this book was published, the
molecular revolution has continued. DNA has been named by Time
magazine as the Molecule of the Year, a Nobel Prize has been awarded
to a young man for the invention of the polymerase chain reaction, and
television viewers have learned of the DNA fingerprint. Molecular
technology in medicine is increasing. The availability of DNA probes
for cancer susceptibility is stressing our system of insurance, testing
our ideas about medical ethics, and teaching us new things about can
cer. In this edition, I have added a number of new sections, as well as a
new chapter. New examples of molecular medicine have been added to
demonstrate current applications of this technology. The basic con
cepts of molecular biology remain the basis for the first three chapters
of the book. The excitement surrounding molecular medicine that I
mentioned in the preface to the first edition continues. It is now tinged
with a touch of awe and a little bit of fear at the changes that recombi
nant DNA technology have brought to our society.
Dennis W Ross, M.D., Ph.D.
Winston-Salem, North Carolina
Preface to the First Edition
This book describes the discoveries that have created a field called mo
lecular medicine. The use of recombinant DNA technology in medical
research and most recently in medical practice constitutes a revolu
tionary tool in our study of disease. Probing the human genome is rap
idly becoming as routine as looking at cells under the microscope. The
cloning of a new gene is now a common occurrence, newspapers re
port. Recombinant DNA technology, like the invention of the micro
scope, shows us a world of detail richer than we might have imagined.
This book presents the discoveries, basic scientifiic concepts, and
sense of excitement that surround the revolution in molecular medi
cine. The scientific basis of molecular medicine is explained in a sim
ple and direct way. The level of technical detail, however, is sufficient
for the reader to appreciate the power of recombinant DNA technology.
This book is clinically oriented throughout. All of the examples and
applications are related to medical discoveries and new methods of di
agnosis and therapy. A few subjects within molecular medicine are ex
amined in more detail to allow the reader to become aware of the
strengths and shortcomings of a molecular approach to disease. I do
not hide the incomplete understanding that still surrounds many of the
recent discoveries in molecular medicine.
I intend to demonstrate the concepts of molecular medicine in this
book by showing examples from all branches of medicine. I include,
for instance, infectious diseases, genetic disorders, and cancer. How
ever, I am not trying to be comprehensive in examining all areas of mo
lecular medicine. So many discoveries are made each week in this field
that it is not yet possible to draw them together in a comprehensive
volume. My goal is to help the reader understand what the future may
hold as well as the most important current applications.
Dennis W Ross, M.D., Ph.D.
Winston-Salem, North Carolina
Acknowledgments
I wish to thank many people who have made useful suggestions and
sustained warm discussions that have improved this third edition.
Medical students have taught me, while I was in the apparent act of try
ing to teach them. Special thanks to Angela Bartley and Tehnaz Parakh.
The cancer patients that I have worked with have demonstrated to me
the need to turn research into medicine. My medical colleagues in
cluding: Malcolm Brown, David Collins, Joseph Dudley, Tommy Simp
son, and Edward Spudis have tolerating my practicing exposition on
them. Dr. Gordon Flake deserves special thanks for long continuing as
sistance to this book and its sister Introduction to Oncogenes and Mol
ecular Cancer Medicine (Springer 1998). Laura Gillan, my editor at
Springer, made me do it. At a time when I was not sure I could encom
pass all that was happening, she said, "just keep it simple" and I tried.
All of the illustrations in this third edition are new. David Pounds, a
medical illustrator, has taken all of the figures done by me in the earlier
editions and re-interpreted or replaced them with drawings that are
both more artistic and more correct. Finally, I need to thank my wife of
32 years, Suzie Ross, for the enduring encouragement and very real
support of my writing and my career.
Dennis W Ross, M.D., Ph.D.
Winston-Salem, North Carolina
Contents
Preface to the Third Edition ..................... v
Preface to the Second Edition . . . . . . . . . . . . . . . . . . .. vii
Preface to the First Edition ...................... ix
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
I. BASICS OF MOLECULAR BIOLOGY
1. Human Genome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Overview. The Genetic Message. Information Content of the Genome
• Open Reading Frame, ORF • Genome versus Library. Anatomy of a
Gene. BRCAl • C-MYC • INS. Junk DNA. Gene Maps. Physical
Organization of the Genome. Basic Genetics • Alleles and Inheritance
• Polygenic Traits. Human Genome Project. Aside: What the Genome
Does Not Code For. Summary
2. Gene Expression and Regulation 22
Overview. DNA Replication. Mitosis and Meoisis • DNA Repair. Muta
tions • Point Mutation. Frame Shift Mutation. Chromosomal Transloca
tion • Aside: Teleomeres and Aging. DNA to Protein. Proteomics • Gene
Expression. Insulin. Cell Signaling Pathway. Summary
3. Genetic Engineering .......................... 35
Overview. Restriction Enzymes. Southern, Northern and Western Blots
• DNA Hybridization. Polymerase Chain Reaction. DNA on a Chip
• Expression Arrays. Antisense Oligonucleotides. Knockout Mice
• Gene Vectors. Cloning Vectors and Gene Therapy of Cystic Fibrosis
• Cloning. Cloning a Gene. Cloning a Human. Choice of Donor Cell
• In Vitro Fertilization. Re-programming • Genetic Engineering of the
Clone. Fertilization. Implantation and Birth. Aside: Human Spare
Parts • Summary
xiv Contents
II. MOLECULAR APPROACH TO DISEASE
4. Infectious Diseases 59
Overview. Microbial Genomcs • Molecular Detection of Microorganisms
• Mini-example: Mycobacteria. HIV - Molecular Monitoring of an
Infection. Molecular Therapy of Infectious Diseases. Antisense
• Ribozymes • Anti Infectious Proteins. Intracellular Single-Strand Anti
bodies. DNA Vaccines. Example-Influenza Virus. Example-Hepatitis
C Virus. Aside: Infectious Vaccines. Genetic Susceptibility to Infection
• Prions • Aside: What Is the Definition of Life in the Genomic Era?
• Biological Terrorism • Summary
5. Inherited Genetic Diseases 75
Overview. Individual Genetic Screening for Inherited Diseases and Risk
Factors. Simple Genetic Diseases. Thrombosis and Factor V Leiden •
Hemochromatosis. Cystic Fibrosis • History of the Discovery of the Cystic
Fibrosis Gene. Genetics of Cystic Fibrosis. Aside: Polygenic Diseases.
Atherosclerosis. apo E • Knockout Mice and Lipid Receptor Transplanta
tion • Diabetes Mellitus. Insulin Gene Transplantation. Summary
6. Immune System and Blood Cells ................ 93
Overview. Clonal Generation of Blood Cells. Molecular Biology of the
Immune System. Immunoglobulin Gene Rearrangement. T-Cell Receptor
Gene Rearrangement. Clinical Laboratory Analysis of Gene Rearrange
ment • Bone Marrow Transplantation. Genetic Engineering of Bone Mar
row Cells. The First Gene Transplant. Aside: Chimeric Man. Summary
7. Cancer ..................................... 108
Overview. Multistep Pathway of Carcinogenesis. Oncogenes. ABL
• MYC • Tumor Suppressor Genes. p53 • BRCAl • Angiogenesis. Tissue
Invasion and Metastasis. Colon Cancer: Model of a Multistep Process
• Squamous Cell Carcinoma of the Uterine Cervix: Model of Viral Role in
Cancer. HPV • Anti-HPV Cancer Vaccine. Lymphoma and Leukemia.
Chronic Myeloid Leukemia. Registrar's Analogy. BCR/ABL. Follicular
Lymphoma. Burkitt's Lymphoma. Molecular Therapy of Cancer. Anti
sense Oligonucleotide Therapy of C-MYC • Adenovirus Killing of p53 De
ficient Cancer Cells. Antibodies to Oncoproteins and Tumor Antigens.
Summary
8. Molecular Therapeutics 131
Overview. Pharmacogenetics. SNP's • Cytochrome P450 System
• Drug Development. High-throughput Screening Technologies. STI571
(Gleevec}-A Specific Inhibitor of BCR/ABL. Gene Therapy. Mini-
Contents xv
examples. Hemophilia and Factor IX Replacement. Immunotherapy of
Lymphoma/Leukemia. Suicide Gene Therapy of Tumors. Graft versus
Host Therapy of Leukemia. Molecular Production of Drugs. Antisense
• Recombinant Drugs. Pharmed Drugs. Mini-examples. CEA Antigen in
Cereals. Aside: Franken Foods. Biomaterials and Tissues. Embryonic
Stem Cells
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 144
Glossary .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 147
Index ....................................... 151