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OXFORD MONOGRAPHS ON MEDICAL GENETICS

GENERAL EDITORS

Arno G. Motulsky
Peter S. Harper
Charles Scriver
Charles J. Epstein
Judith G. Hall

16. C.R. Scriver and B. Childs: Garrod’s inborn factors in disease

18. M. Baraitser: The genetics of neurological disorders
21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal development: an atlas
22. J.J. Nora, K. Berg, and A.H. Nora: Cardiovascullar diseases: genetics, epidemiology, and prevention
24. A.E.H. Emery: Duchenne muscular dystrophy, second edition
25. E.G.D. Tuddenham and D.N. Cooper: The molecular genetics of haemostasis and its inherited disorders
26. A. Boué: Fetal medicine
30. A.S. Teebi and T.I. Farag: Genetic disorders among Arab populations
31. M.M. Cohen, Jr.: The child with multiple birth defects
32. W.W. Weber: Pharmacogenetics
33. V.P. Sybert: Genetic skin disorders
34. M. Baraitser: The genetics of neurological disorders, third edition
35. H. Ostrer: Non-mendelian genetics in humans
36. E. Traboulsi: Genetic diseases of the eye
37. G.L. Semenza: Transcription factors and human disease
38. L. Pinsky, R.P. Erickson, and R.N. Schimke: Genetic disorders of human sexual development
39. R.E. Stevenson, C. E. Schwartz, and R.J. Schroer: X-linked mental retardation
40. M.J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the 21st century
41. J. Weil: Psychosocial genetic counseling
42. R.J. Gorlin, M.M. Cohen, Jr., and R.C.M. Hennekam: Syndromes of the head and neck, fourth edition
43. M.M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes
44. R.A. King, J.I. Rotter, and A.G. Motulsky: The genetic basis of common diseases, second edition
45. G.P. Bates, P.S. Harper, and L. Jones: Huntington’s disease, third edition
46. R.J.M. Gardner and G.R. Sutherland: Chromosome abnormalities and genetic counseling, third edition
47. I.J. Holt: Genetics of mitochondrial diseases
48. F. Flinter, E. Maher, and A. Saggar-Malik: The genetics of renal disease
49. C.J. Epstein, R.P. Erickson, and A. Wynshaw-Boris: Inborn errors of development
50. H.V. Toriello, W. Reardon, and R.J. Gorlin: Hereditary hearing loss and its syndromes, second edition
51. P.S. Harper: Landmarks in medical genetics
52. R.E. Stevenson and J.G. Hall: Human malformations and related anomalies, second edition
53. D. Kumar and S.D. Weatherall: Genomics and clinical medicine
Genomics and
Clinical Medicine

EDITED BY

Dhavendra Kumar, MD, FRCI, FACMG

Institute of Medical Genetics
University Hospital of Wales
Cardiff University
Cardiff, Wales
United Kingdom

ADVISORY EDITOR

Professor Sir David Weatherall, DM, FRS

Weatherall Institute of Molecular Medicine
John Radcliffe Hospital
Oxford University
Oxford, England
United Kingdom

AC
2008
AC
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electronic, mechanical, photocopying, recording, or otherwise,
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Library of Congress Cataloging-in-Publication Data

Genomics and clinical medicine / [edited by]
Dhavendra Kumar and Sir David Weatherall.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-19-518813-4
1. Medical genetics. 2. Genomics. I. Kumar, Dhavendra. II. Weatherall, D. J.
[DNLM: 1. Genomics. 2. Clinical Medicine. 3. Genetic Predisposition to Disease.
4. Pharmacogenetics. QU 58.5 G3352 2007]
RB155.G464 2007
6160 .042–dc22 2006034212

987654321

Printed in China
on acid-free paper
To Anju, who encourages me to write, and Ashish and Nikita, who make me proud
This page intentionally left blank
Foreword
A scant 20 years have passed since the word ‘‘genomics’’ was coined are associated with proven means of reducing risk through diet,
by Victor McKusick, Frank Ruddle, and Tom Roderick to describe a exercise, lifestyle change, medical surveillance, or pharmacotherapy,
new discipline. The suffix of the word derives from the Greek ome the real likelihood of widespread individualized programs of pre-
meaning all, and aptly conveyed an intention to transition the study ventive medicine grows by the day. Similarly, the ability to make
of heredity from a focus on single genes (genetics) to the more global predictions about the possibility of a beneficial or undesirable re-
perspective of all of the hereditary material. A proliferation of sponse to drug therapy, the field of pharmacogenomics, is advancing
other ‘‘omics’’ disciplines has subsequently erupted—including pro- rapidly, and will soon require healthcare providers to determine the
teomics, metabolomics, transcriptomics, glycomics, microbiomics, genotype before writing the prescription, at least for certain drugs.
and many more. Many of us predict that the complete genome sequence of an indi-
However, genomics remains the foundation of the rest, reflect- vidual will become part of that person’s medical record within
ing as it does a comprehensive analysis of the deoxyribonucleic acid approximately 10 years, at a cost of $1000 or less. And the therapeu-
(DNA) instruction book. The success of the Human Genome Project tics that we use in the future will likely be heavily dependent on an
has now laid that instruction book wide open. As a result, the life understanding of the genomic basis of illness, leading to interven-
sciences have been catapulted forward, and biology has now taken its tions that are both more accurately targeted to the underlying prob-
rightful place alongside physics and chemistry as a truly digital and lem and less likely to cause side effects.
quantitative science. All of these advances should be welcomed by anyone interested
It is the application of genomics to medicine that carries its in the alleviation of human suffering. Yet, a number of major ethical,
greatest promise of benefit to humankind. Thus, the publication of legal, and social challenges lie along the path if this vision is going to
this first textbook of ‘‘Genomics and Clinical Medicine’’ marks a be realized. In the United States, for example, we still lack effective
milestone, a coming of age. Here, in the early years of the third federal legislation to prevent discriminatory uses of predictive ge-
millennium, we can see the emerging outlines of a new synthesis of netic information. Major challenges also lie ahead with regard to
the noble tradition of the healing arts with an increasingly precise ensuring equitable access to new genomic technologies, especially as
way of understanding the causes of disease, based on an understand- our medical care system seems to undervalue opportunities for
ing of the human genome. preventive medicine, focusing instead on treating disease once it
For some in the clinical medicine community, however, this has already appeared. However, perhaps the greatest barrier, and the
textbook may come as a surprise. After all, there are still many one which this book admirably seeks to address, is an educational
practicing physicians who would say they see no evidence of genetics one. Most members of the public are interested in genomics, but
or genomics as part of their daily medical practice. Surely, however, relatively unsure of the details. Seeking advice, they generally turn to
that reveals a problem with the successful communication of rapid their healthcare providers, but many of those professionals are
new developments in this field, not the facts of the matter. For in poorly prepared to become practitioners of this new art. After all,
these 41chapters, a vast array of genomic implications for nearly most physicians have had little or no training in genetics or geno-
every condition that affects humankind is laid out in an elegant and mics, and will be hard pressed to quickly acquire the scientific
comprehensive fashion. principles, the medical knowledge, and the psychosocial skills that
The pace of progress in genomics has been astounding. Over will be necessary for the successful introduction of genomic medi-
just the last 15 years, largely as a consequence of the tools made cine. Busy practitioners will desperately need an authoritative source
available through the Human Genome Project, genes have been of information that includes both principles and specific applica-
identified for more than 2000 inherited conditions. With recent tions. The introduction of this textbook, with its distinguished and
rapid advances in the understanding of human genetic variation, authoritative list of contributors, thus arrives in the nick of time.
the specific hereditary contributions to common diseases like diabe- Welcome to the genome era.
tes, heart disease, cancer, and mental illness are emerging at an
unprecedented rate. The very real possibility of offering individuals, Francis S. Collins, MD, PhD
who are currently healthy, a personalized prediction of future risks of National Human Genome Research Institute
illness is no longer a distant dream. And given that, many of the National Institutes of Health
common disorders for which predictions are becoming possible Bethesda, MD, USA
This page intentionally left blank
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Preface
Although the science of genetics is only 150 years old, genetics has and mortality. In addition, a number of infectious diseases are
been in existence since ancient time. The evolution and natural associated with genomic mutations manifesting in the form of
selection theories put forward by Charles Darwin had clear over- increased susceptibility, clinical severity, favorable and unfavorable
tones reflected in some of our present-day concepts of the genetic response to antimicrobial therapy, and in conferring protection. It is
basis of biological life. Mendel’s laws of inheritance, and successive possible that the protective effect of a microbial vaccine might be
discoveries in various aspects of genetics, laid the foundations of a influenced by genomic variation.
number of disciplines covering different areas within the science of The sequence of the entire human genome is now complete, but
genetics. Human genetics was no exception. However, this remained this is not limited to one individual alone. Each person carries a
heavily shrouded under the dark clouds of the so-called Eugenics distinct sequence. The variation among all humans is reflected in
movement of the early twentieth century, when history recorded one variation within the human genome. The genomic variation be-
of the worst practical applications of modern science on fellow tween individuals, together with environmental factors probably
human beings under the pretext of scientific research. determines the disease susceptibility and is important in drug effica-
It has taken almost 60 years to arrive at our present state in the cy and side effects (Chakravati, 2000; Holden, 2000). The key to
science of genetics. The future now appears bright, opening up many genomic variation lies in finding single nucleotide polymorphisms
opportunities on the horizon. Clinical genetics is now a recognized (SNPs) and its use in disease association studies (Stephens et al.,
medical specialty among several disciplines comprising the current 2001). The positional cloning (identifying the gene by location
spectrum of modern medicine. The basis of clinical genetics is followed by functional analysis) of the disease susceptibility loci
grounded in the sound knowledge and understanding of medical will depend upon the successful application of haplotype associa-
genetics, which emerged as a spin-off of ‘‘Human Genetics.’’ tions. In addition, these will be important in clinical studies to find
Fifty years after the discovery of the double-helix structure of individuals in whom a drug is likely to be efficacious. The use of SNPs
the deoxyribonucleic acid (DNA) molecule (Watson and Crick, in pharmacogenetics is currently restricted to studying genes for
1953), characterization of the complete sequence and organization drug-metabolizing enzymes, such as P450s, and variations in genes
of the human genome was successfully accomplished (Lander et al., that target drug receptors. The newly emerging dynamic field of
2001; Venter et al., 2001). This major scientific achievement laid the pharmacogenomics is an exciting application of genomic variation
foundation of ‘‘human genomics’’; that section of the biological in drug discovery and drug development.
sciences, which studies variations, mutations, and functions of The recent cloning of real disease susceptibility genes for mul-
genes and controlling regions, and their implications on human tifactorial diseases is encouraging, for example, the identification of
variation, health, and disease. This is strengthened by developments NOD2 as a susceptibility gene for Crohn’s disease (Hugot et al., 2001;
in the other areas of genomics relating to bacteria, vectors, parasites, Ogura et al., 2001). This is a major development in understanding
animals, and plants. the pathophysiology of inflammatory bowel disease. Similar studies
The identification of all human genes and their regulatory are likely to unravel the genetic mechanisms in other complex
regions provides the essential framework in our understanding of medical diseases. A comprehensive SNP map will allow the cloning
the molecular basis of disease. This advance has also provided a firm of other susceptibility alleles. However, this will depend upon popu-
foundation for the future development of genomic technologies that lation sample and size, the method employed, linkage disequilibri-
can be applied to modern medical science. Rapid developments in um, or association studies rather than the technology used (Cardon
global gene analysis, gene product analysis, medical bioinformatics, and Bell, 2001). Some of the best genetic studies of this kind include
and targeted molecular genetic testing are destined to change the susceptibility to infectious disease, for example, an association be-
practice of modern medicine. However, many practicing clinicians tween chemokine receptors (CCR5) and human immunodeficiency
perceive developments in genomics as primarily confined to the virus (HIV) susceptibility, and between the bacterial transporter
research arena with little clinical applicability. DNA/ribonucleic protein Nramp and resistance to macrophage-infecting bacteria
acid (RNA)-based methods of disease susceptibility screening, mo- such as Mycobacterium tuberculosis. Similarly, various alleles at the
lecular-based disease diagnosis and prognosis, and genomics-based G6PDH locus determine malaria susceptibility (Tishkoff et al.,
therapeutic choices and prediction of treatment outcome are some 2001).
of the key areas that are likely to influence the practice of modern These kinds of studies and clinical applications of the resulting
clinical medicine. outcomes are not without ethical concerns. Some of the questions
Undoubtedly, the science of genomics holds tremendous po- and concerns are related to ownership of the genes and freedom to
tential for improving human health. The World Health Organiza- use collected DNA for such studies. These are complex and emo-
tion (WHO, 2002) has recently made several recommendations on tional issues, especially when dealing with populations who may
the scope and application of genomics on global health. It is have been exploited or perceived to have been exploited. These issues
acknowledged that the information generated by genomics will should always be dealt with carefully under the statutory require-
provide major benefits in the prevention, diagnosis, and manage- ments and rules.
ment of communicable and genetic diseases as well as other common There has been a tremendous surge in various subspecialties
medical diseases, including cardiovascular diseases, cancer, diabetes, and technologies with names ending in -omics. We are rapidly
and mental illnesses (Cardon and Bell, 2001). Together, these moving into the ‘‘omics’’ era. In addition to genomics, several new
constitute the major health burden, as reflected in chronic ill health specialist fields with an ‘‘omics’’ suffix have recently appeared, for
x Preface

example, pharmacogenomics, nutrigenomics, metabonomics, tran- could these be applied and delivered to the 95% of human diseases
scriptomics, proteomics, microbiomics, glycomics, toxicoge- that do not fall under the rubric of genetic disorders? These are some
nomics, and many more. Some of these areas are included in this of the likely questions related to genomic medicine. Medical and
book. Whatever the basis of distinction might be, the driver of all public health professionals urgently need to make the changes nec-
these terms is GENOMICS—the study of genomes in its entirety. essary to accommodate rapid identification and characterization of
Genomics is not just about genome sequencing. Apart from the numerous genomic variants at multiple loci, which increase or
full-length complementary DNAs (cDNAs) and their sequences, decrease the risks for various diseases, singly or in combination with
copies of messenger RNAs (mRNAs) that actually exist and code other genes, and with various chemical, physical, infectious, phar-
for different proteins are probably more important. The study of macologic, and social factors (Khoury, 1999). This genetic and
proteins thus derived, falls within the broad field of proteomics, a genomic information is crucial in assessing the disease susceptibility
likely outcome of functional genomics and probably a true compan- among healthy individuals, and in personalized primary and sec-
ion to genomics. It is likely that eventually proteomics will have more ondary prevention planning. Collins and McKusick (2001) stated
practical applications in clinical medicine. This is rapidly moving that, ‘‘By the year 2010, it is expected that predictive genetic tests will
ahead with the completion of the HapMap Project (International be available for as many as a dozen common conditions, allowing
HapMap Consortium, 2005) and the future ‘‘functional-variant individuals who wish to know this information to learn their risks for
database,’’ a natural outcome of the HapMap Project (Gibbs, 2005). which interventions are or will be available. Such interventions could
It is vital that existing gaps in our knowledge about various take the form of medical surveillance, lifestyle modifications, diet, or
‘‘omics’’ disciplines are filled to ensure efficient use of the valuable drug therapy. Identification of persons at highest risk for colon
information emerging from research. It is also important that the cancer, for example, could lead to targeted efforts to provide colono-
gap between ‘‘genetic professionals’’ and the ‘‘primary-care commu- scopic screening to those individuals, with likelihood of preventing
nity,’’ and as well as the ‘‘public health community,’’ is narrowed many premature deaths.’’
(Khoury et al., 2003). Integration of this knowledge in the medical Personalized medicine will encompass not only common med-
education curriculum and the continued professional education ical diseases, but could include a wide range of preventable diseases
programs is urgently required to ensure applications of genomics (www.genovations.com). Genetic testing for future disease suscep-
in the provision of healthcare. tibility using multiple genomic variants will be possible and afford-
During the last two decades, the practice of medical genetics or able with the application of ‘‘high-throughput’’ microarrays-based
clinical genetics, has found its niche within the broad horizon of genetic testing (Collins and Guttmacher, 2001).
clinical medicine. Genetic services now constitute a small, but albeit A wealth of information on genomics is rapidly being acquired
important, component of modern medical practice and public with the potential for major impact on human health. However, this
health. Currently, genetic services focus on providing information data and information is scattered throughout several scientific jour-
on chromosomal and single-gene diseases with limited contribution nals, reviews, and state-sponsored reports and bulletins. A clinician
to multifactorial/polygenic diseases. How would this then be differ- or health professional often has difficulty in accessing and assimilat-
ent from genomics? Already, there is tremendous enthusiasm for the ing this information for application in the medical and public health
recently introduced term of ‘‘genomic medicine.’’ In a primer on practice. More importantly, an inability to assimilate and interpret
genomic medicine, Guttmacher and Collins (2002) viewed ‘‘genetics leads to frustration and avoidance of potentially useful information.
as the study of single genes and their effects’’ and genomics as ‘‘the In view of the above developments and the rapidly increasing
study not just of single genes, but of the functions and interactions of gulf in the available literature resource, the need for a dedicated book
all the genes in the genome.’’ In simple terms, there is a quantitative on genomic medicine was appreciated. It was obviously an impossi-
difference between the two fields—the study of multiple genes as ble task for a single author. Several leading experts in different fields
opposed to that of one gene. Thus, genetics can be seen as part of of the genome science and technology offered to contribute. The
genomics! However, there is a qualitative difference between genet- views and opinions reflected in individual chapters are largely influ-
ics and genomics in medical and health applications ranging from enced by their own experience, perception, and interpretation of the
the concept of disease in genetics to the concept of information in available data and information.
genomics (Khoury et al., 2003). This book provides a wide coverage of the subject from the
The practice of medical genetics has traditionally focused on historical progress to general aspects of genomics and the describing
those conditions that result from specific alterations or mutations in in some detail the medical and health applications. Generally, all
single genes (e.g., inborn errors of metabolism, Duchenne muscular chapters follow a similar format and are written by experts in their
dystrophy, and Huntington’s disease), whole or part of chromo- respective field of research and clinical expertise. Each chapter pro-
somes (e.g., trisomy 21 in Down syndrome), or associated with vides a detailed and comprehensive account of the subject. However,
congenital malformations and developmental disabilities. The exist- it is likely that some gap might exist due to inevitable time lag
ing model of medical genetic services for these conditions includes between the time of writing and appearing in the print. This is due
laboratory diagnosis, genetic counseling, and management. This is to rapid developments in each field. However, all efforts are being
supported by public health measures to ensure delivery of genetic made to provide the reader core information on the basic principles,
services and genetic screening (e.g., newborn screening or screening scientific facts, current and likely future applications, useful relevant
the high-risk population). On the other hand, the practice of geno- references, and information on Internet-based resources that should
mics in medicine and public health will focus on information result- be helpful in exploring the subject further.
ing from variation at one or multiple loci and strong interactions It is hoped that this book will facilitate in acquiring factual
with environmental factors, for example, diet, drugs, infectious information on genomics, developing concepts on the genomic
agents, chemicals, physical agents, and behavioral factors (Khoury basis of human disease, and in providing a practical base to enable
et al., 2003). an interested clinician and health professional to develop an under-
What medical and public health applications could one foresee standing of applications of genomics in clinical medicine and health.
following the completion of human genome sequence in 2003? How It is aimed at a wide range of scientists, clinicians, and health
 Preface xi

professionals who are engaged in research, teaching, and training in provides the basis of individual variability and the modern postge-
medical and health applications of the genome-based science and nomic clinician will need to ensure that this is applied as an art.
technology.
Finally, the practice of Medicine is an art based on sound Dhavendra Kumar MD, FRCPI, FACMG
scientific principles. It would be appropriate to quote Sir William Institute of Medical Genetics
Osler’s remarks, ‘‘If there were no individual variability, medicine University Hospital of Wales
would have been science not an art.’’ Genomics in this context Cardiff University, Cardiff, Wales, UK

References
Cardon, LR and Bell, JI (2001). Association study designs for complex diseases. Khoury, MJ (1999). Human genome epidemiology: translating advances in
Nat RevGenet, 2:91–99. human genetics into population-based data for medicine and public health.
Chakravati, A (2000). To a future of genetic medicine. Nature, 409:822–823. Genet Med, 1:71–73.
Collins, FS and Guttmacher, AE (2001). Genetics moves into medical Khoury, MJ, McCabe LL, and McCabe, ER (2003). Population screening in the
mainstream. JAMA, 286:2322–2324 age of genomic medicine. N Engl J Med, 348:50–58.
Collins, FS and McKusick, VA (2001). Implications of the Human Genome Lander, ES, et al. (2001). Initial sequencing and analysis of the human genome.
Project for medical science. JAMA, 285:540–544. International Human Genome Sequencing Consortium. Nature, 409:860–921.
Genovations—the advent of truly personalized healthcare. Available: http:// Ogura, Y et al. (2001). A frameshift in NOD2 associated with susceptibility to
www.genovations.com [ July 12, 2007]. Crohn’s disease. Nature, 411:603–606.
Gibbs, R (2005). Deeper into the genome. Nature, 437:1233–1234. Stephens, C et al. (2001). Haplotype variation and linkage disequilibrium in 313
Guttmacher, AE and Collins, FS (2002). Genomic medicine: a primer. N Engl J human genes. Science, 293: 489–493.
Med, 347:1512–1520. Tishkoff, SA et al. (2001). Haplotype diversity and linkage disequilibrium at the
Holden, AL (2000). The SNP consortium: a case study in large pharmaceutical human G6PDH: recent origin of alleles that confer malarial resistance.
company research and development collaboration. J Com Biotech, Science, 293:455–461.
6:320–324. Venter, JC et al. (2001). The sequence of the human genome. Science, 291:1304–1351.
Hugot, JP, et al. (2001). Association of NOD2 leucine-rich variants with Watson, JD and Crick, FHC (1953). Molecular structure of nucleic acids.
susceptibility to Crohn’s disease. Nature, 411:599–603. Nature, 171:737–738.
International HapMap Consortium (2005). A haplotype map of the human World Health Organization (2002). Genomics and world health—report from
genome. Nature, 437:1299–1320. the advisory committee on health research. WHO, Geneva.
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Acknowledgments
Editing a multiauthor book was a huge challenge. This was impossi- to Mr. Bill Lamsback, the Senior Executive Editor at the New York
ble without the support of several people particularly when a large office of the Oxford University Press, who believed in the book project
team of expert contributors was involved. Although my idea of from start and supported it throughout to its final production.
producing a book on genomic medicine looked attractive, it raised I am indebted to Dr. Annie Procter and Prof. Julian Sampson,
several questions. As for me, this was indeed daunting but convinc- both at the Institute of Medical Genetics, Cardiff, for providing me
ing enough to approach several authors and advisors. The proposal generous time, space, and essential resources in the completion of
for this book was positively considered by several leading publishers this book. Several of my colleagues in Cardiff spent hours reviewing
and as well as few key experts in the fast-emerging virgin territory of the manuscript. I am particularly grateful to Drs. Annie Procter,
genomic medicine. I will always remain truly grateful to all expert Daniela Piltz, Mark Tein, Alex Murray, Mark Davies, Andrea
reviewers, contributors, as well as strong support from the Oxford Edwards, and Prof. Angus Clarke for critically reviewing some
University Press in bringing my dream to fruition. chapters. Other staff members were always enthusiastic, positive,
Several eminent persons offered wise counsel during the early and supportive of this project.
stages of book planning. Notable names include Prof. Sir David My special thanks are due to Ms. Cetra Hastings, who worked
Weatherall (Oxford), Prof. John Bell (Oxford), Prof. Michael Patton tirelessly as a secretary and offered valuable and constructive
(London), Prof. Michael Parker (Oxford), and Prof. Stuart Tanner editorial advice, even while working away as an English language
(Sheffield). Their invaluable advice, support, and encouraging and expert in Norway (originally from Oxford).
positive responses were a good kick-start. The book is dedicated to all lead authors and their team of
I was privileged to receive support from Prof. Francis Collins coauthors who worked extremely hard in writing excellent chapters.
(Director, NHGRI, NIH, USA) on this idea for a comprehensive The quality of the material presented in almost all chapters is
book dealing with genomic medicine. He very kindly agreed to write exemplary and of very high standards. I will always remain grateful
the foreword for the book. I was fortunate to have a regular flow of to all those whose name I might have omitted, but without their
suggestions and reflections from some leading experts including Prof. support and encouragement this book could not have been con-
Colin Munro (Glasgow), Prof. Peter Harper (Cardiff), Dr. Eli Hatch- ceived, written, and produced.
well (New York), Prof. David Cooper (Cardiff), Prof. Angus Clarke Finally, this book could not have been completed without the
(Cardiff), and Prof. Julian Sampson (Cardiff). I was extremely fortu- affection and support of my family who stood beside me like a
nate to receive continuous flow of expert editorial guidance and buttress till the final draft of the manuscript was mailed to the Oxford
supervision from Prof. Sir David Weatherall. Special thanks are due University Press.
This page intentionally left blank
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