Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases

By Jules J. Berman

Rare Diseases and Orphan Drugs shows that much of what we now know about common diseases has been achieved by studying rare diseases. It proposes that future advances in the prevention, diagnosis, and treatment of common diseases will come as a consequence of our accelerating progress in the field of rare diseases.

Understanding the complex steps in the development of common diseases, such as cancer, cardiovascular disease, and metabolic diseases, has proven a difficult problem. Rare diseases, however, are often caused by aberrations of a single gene. In rare diseases, we may study how specific genetic defects can trigger a series of events that lead to the expression of a particular disease. Often, the disease process manifested in a certain rare disease is strikingly similar to the disease process observed in a common disease.

This work ties the lessons learned about rare diseases to our understanding of common ones. Chapters covering the number of common diseases are minimized, while rare diseases are introduced as single diseases or as members of diseases classes. After reading this book, readers will appreciate how further research into the rare diseases may lead to new methods for preventing, diagnosing, and treating all diseases, rare or common.

• Makes rare diseases relevant to clinicians and researchers by tying lessons learned about the rare diseases to our understanding of the common diseases
• Stresses basic pathologic mechanisms that account for human disease (e.g., disorders of cell development, replication, maintenance, function and structure), that can be understood without prior training in pathology
• Discusses advanced concepts in molecular biology and genetics in a simple, functional context appropriate for medical trainees and new researchers
• Offers insights into how further research into rare diseases may lead to new methods for preventing, diagnosing, and treating all diseases

• Language: English
• Publisher: Academic Press
• Release date: May 26, 2014
• ISBN: 9780124200098

Jules J. Berman

Jules Berman holds two Bachelor of Science degrees from MIT (in Mathematics and in Earth and Planetary Sciences), a PhD from Temple University, and an MD from the University of Miami. He was a graduate researcher at the Fels Cancer Research Institute (Temple University) and at the American Health Foundation in Valhalla, New York. He completed his postdoctoral studies at the US National Institutes of Health, and his residency at the George Washington University Medical Center in Washington, DC. Dr. Berman served as Chief of anatomic pathology, surgical pathology, and cytopathology at the Veterans Administration Medical Center in Baltimore, Maryland, where he held joint appointments at the University of Maryland Medical Center and at the Johns Hopkins Medical Institutions. In 1998, he transferred to the US National Institutes of Health as a Medical Officer and as the Program Director for Pathology Informatics in the Cancer Diagnosis Program at the National Cancer Institute. Dr. Berman is a past President of the Association for Pathology Informatics and is the 2011 recipient of the Association’s Lifetime Achievement Award. He is a listed author of more than 200 scientific publications and has written more than a dozen books in his three areas of expertise: informatics, computer programming, and pathology. Dr. Berman is currently a freelance writer.

Book preview

Rare Diseases and Orphan Drugs

Keys to Understanding and Treating the Common Diseases

First Edition

Jules J. Berman, Ph.D., M.D.

Table of Contents

Cover image

Title page

Copyright

Dedication

Acknowledgments

Foreword

Preface

Content and Organization of the Book

Rules Governing the Rare Diseases

Who Should Read this Book?

How to Read this Book

Chapter 1. What are the Rare Diseases, and Why do we Care?

Abstract

1.1 The definition of rare disease

1.2 Remarkable progress in the rare diseases

References

Chapter 2. What are the Common Diseases?

Abstract

2.1 The common diseases of humans, a short but terrifying list

2.2 The recent decline in progress against common diseases

2.3 Why medical scientists have failed to eradicate the common diseases

References

Chapter 3. Six Observations to Ponder while Reading this Book

Abstract

3.1 Rare diseases are biologically different from common diseases

3.2 Common diseases typically occur in adults; rare diseases are often diseases of childhood

3.3 Rare diseases usually occur with a Mendelian pattern of inheritance. common diseases are non-Mendelian

3.4 Rare diseases often occur as syndromes, involving several organs or physiologic systems, often in surprising ways. common diseases are typically non-syndromic (see Section 10.1)

3.5 Environmental factors play a major role in the cause of common diseases; less so in the inherited rare diseases

3.6 The difference in rates of occurrence of the rare diseases compared with the common diseases is profound, often on the order of a thousand-fold

3.7 There are many more rare diseases than there are common diseases

References

Chapter 4. Aging

Abstract

4.1 Normal patterns of aging

4.2 Aging and immortality

4.3 Premature aging disorders

4.4 Aging as a disease of non-renewable cells

References

Chapter 5. Diseases of the Heart and Vessels

Abstract

5.1 Heart attacks

5.2 Rare desmosome-based cardiomyopathies

5.3 Sudden death and rare diseases hidden in unexplained clinical events

5.4 Hypertension and obesity: quantitative traits with cardiovascular co-morbidities

References

Chapter 6. Infectious Diseases and Immune Deficiencies

Abstract

6.1 The burden of infectious diseases in humans

6.2 Biological taxonomy: where rare infectious diseases mingle with the common infectious diseases

6.3 Biological properties of the rare infectious diseases

6.4 Rare diseases of unknown etiology

6.5 Fungi as a model infectious organism causing rare diseases

References

Chapter 7. Diseases of Immunity

Abstract

7.1 Immune status and the clinical expression of infectious diseases

7.2 Autoimmune disorders

References

Chapter 8. Cancer

Abstract

8.1 Rare cancers are fundamentally different from common cancers

8.2 The dichotomous development of rare cancers and common cancers

8.3 The Genetics of Rare Cancers and Common Cancers

8.4 Using rare diseases to understand carcinogenesis

References

Chapter 9. Causation and the Limits of Modern Genetics

Abstract

9.1 The inadequate meaning of biological causation

9.2 The complexity of the so-called monogenic rare diseases

9.3 One monogenic disorder, many genes

9.4 Gene variation and the limits of pharmacogenetics

9.5 Environmental phenocopies of rare diseases

References

Chapter 10. Pathogenesis: Causation’s Shadow

Abstract

10.1 The mystery of tissue specificity

10.2 Cell regulation and epigenomics

10.3 Disease phenotype

10.4 Dissecting pathways using rare diseases

10.5 Precursor lesions and disease progression

References

Chapter 11. Rare Diseases and Common Diseases: Understanding their Fundamental Differences

Abstract

11.1 Review of the fundamentals in light of the incidentals

11.2 A trip to Monte Carlo: how normal variants express a disease phenotype

11.3 Associating genes with common diseases

11.4 Mutation versus variation

References

Chapter 12. Rare Diseases and Common Diseases: Understanding their Relationships

Abstract

12.1 Shared genes

12.2 Shared phenotypes

References

Chapter 13. Shared Benefits

Abstract

13.1 Shared prevention

13.2 Shared diagnostics

13.3 Shared cures

References

Chapter 14. Conclusion

Abstract

14.1 Progress in the rare diseases: social and political issues

14.2 Smarter clinical trials

14.3 For the common diseases, animals are poor substitutes for humans

14.4 Hubris

References

Appendix I. List of Genes Causing More than One Disease

Appendix II. Rules, Some of Which are Always True, and All of Which are Sometimes True

Do-it-yourself rules

References

Glossary

References

Index

Copyright

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Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administrations, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication.

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Dedication

For my mother, Ida

Acknowledgments

It is impossible to deeply understand the rare diseases, or their relationships to the common diseases, without access to the OMIM data set. OMIM, the Online Mendelian Inheritance in Man, is almost certainly the largest, best-curated, and longest-running collection of information on Mendelian disorders and disease genes. OMIM began simply as MIM in the early 1960s, a creation of Dr. Victor A. McKusick. Starting in 1966, it was printed in annual volumes. By 1998, the print version was heavier than most people could safely lift. Currently, it is available as a query engine online, and as a file that can be downloaded at no cost, and studied as a stand-alone plain-text document. The current length of OMIM is about 175 megabytes, and is curated at the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine, under the direction of Dr. Ada Hamosh. Over my career, I have spent many hundreds of hours, possibly thousands of hours, reading the OMIM file. Without this remarkable resource, I could not have written this book.

I would like to thank the entire staff at the Office of Rare Diseases at the National Institutes of Health. On two separate occasions, these defenders of orphan diseases chose to fund my projects on GIST and on borderline ovarian tumors. This support from the Office of Rare Diseases, received at a time in my career when I was vulnerable to criticism for my preoccupation with orphaned conditions, boosted my resolve and inspired me to follow a path less traveled.

Special thanks go to Mara Conner and Jeffrey Rossetti (Editorial Department), and Caroline Johnson (Production), at Elsevier, for their extraordinary care and effort on this complex book project.

Foreword

Dr. Berman’s book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, addresses a topic of great importance at this particular moment in research history. Recent advances in the molecular biology of disease have taught us that the genetic changes in the common diseases are complex and that there is remarkable variation among affected individuals in the clinical presentation and in the genetic signature of common diseases. Research scientists are beginning to recognize that the common diseases are best conceived as aggregates of many different rare diseases. To benefit from our newly acquired knowledge of the genetics of common diseases, we will need to understand how treatments for the rare diseases will apply to subsets of the common diseases.

Breakthrough discoveries among the rare diseases are now viewed as opportunities to understand and treat the common diseases. Hence, there is an increasing emphasis, coming from government, academia, and private research organizations, to increase funding for rare diseases research and orphan drug development.

Worldwide, orphan drugs are being developed and approved at a rapid rate. In the United States, expedited programs adopted by the FDA should continue to move potential products through the research and development continuum toward approval for safe and effective products. Streamlined programs such as Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review bring optimism to patients and their families for the quick approval of new products. Additional regulatory approaches and incentives have been expanded and include the rare pediatric and tropical diseases priority review vouchers. Repurposed products now qualify for orphan product incentives at the FDA. Compounds included in the Best Pharmaceuticals for Children Act program are eligible for a 6-month extension to existing exclusivity as an incentive to expand the indications for use from the adults to the pediatric population. For antibiotics, a newer incentive program, Generating Antibiotic Incentives Now (GAIN), and authorizing legislation add 5 years to existing exclusivity for products considered new chemical entities and those included under the Orphan Drug Act. The FDA now uses expert consultants to facilitate applications for orphan drugs while still in the pre-approval stage. The success of clinical trials for orphan drugs can be credited, in no small part, to the willingness of individuals with rare diseases to participate in clinical trials.

In the U.S., more than 2,900 active Orphan Product Designations have been made, and 50 additional designations have been provided thus far in 2014. There were 258 Orphan Product Designations in 2013. Obtaining the Orphan Product Designation from the Office of Orphan Products Development at the FDA provides incentives such as 7-year marketing exclusivity, eligibility for research grants, along with exemption from filing fees for some qualifying applications. Pharmaceutical Research and Manufacturers of America reported more than 450 compounds in development for rare diseases. Current activity levels indicate a continued emphasis on rare diseases. Many pharmaceutical companies have established programs to make available the needed orphan products for rare diseases regardless of the patients’ ability to pay for the product.

The U.S. NIH Clinical Center research portfolio contains more than 860 research protocols for approximately 520 rare diseases. In fiscal year 2013, NIH provided $3.456 billion for rare diseases research projects and included approximately $764 million for orphan product research projects.

Our new-generation orphan drugs are designed to target disease-causing pathways that operate in the rare diseases. It is everyone’s hope that these new drugs will prove to be effective against common diseases that share disease pathways with rare diseases. If so, then we can begin to design clinical trials that include common and rare diseases in the same trials.

Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases bridges our understanding of the common diseases and the rare diseases. This unique and much-needed book provides an insightful glimpse of how biomedical research will play out as the rare diseases take an increasing role in the way we understand and treat the common diseases. Healthcare professionals, students, biomedical researchers, and advocates for rare disease research will find that this book applies common sense to a rare subject.

April, 2014

Stephen G. Groft, Pharm.D.

Note added by editor: Dr. Groft retired from the NIH in 2014, where he served as Director of the Office of Rare Diseases Research for more than two decades. His work in the field of rare diseases and orphan drugs began in 1982 at the FDA Office of Orphan Products, a division dedicated to advancing the evaluation and development of therapeutics for the diagnosis and treatment of rare diseases. Dr. Groft served as the Executive Director of the National Commission on Orphan Diseases, from 1987 to 1989. In all, Dr. Groft has played a prominent role in the field of rare diseases and orphan drugs for more than 30 years.

Preface

All interest in disease and death is only another expression of interest in life.

—Thomas Mann

For a few decades now, I have been interested in writing a book that treats the rare diseases as a separate specialty within medicine. Most of my colleagues were not particularly receptive to the idea. Here is a sample of their advice, paraphrased: Don’t waste your time on the rare diseases. There are about 7000 rare diseases that are known to modern medicine. The busiest physician, over the length of a long career, will encounter only a tiny fraction of the total number of rare diseases. Surely, an attempt to learn them all would be silly; an exercise in purposeless scholarship. Furthermore, each rare disease accounts for so few people, it is impractical to devote much research funding to these medical outliers. To get the most bang for our bucks, we should concentrate our research efforts on the most common diseases: heart disease, cancer, diabetes, Alzheimer’s disease, and so on.

Other colleagues questioned whether rare diseases are a legitimate area of study: Rare diseases do not comprise a biologically meaningful class of diseases. They are simply an arbitrary construction, differing from common diseases by a numeric accident. A disease does not become scientifically interesting just by being rare. For some of my colleagues, the rare diseases are mere aberrations, best ignored.

In biology, there are no outliers; no circumstances that are rare enough to be ignored. Every disease, no matter how rare, operates under the same biological principles that pertain to common diseases. In 1657, William Harvey, the noted physiologist, wrote: Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease.

We shall see that the rare diseases are much simpler, genetically, than the common diseases. The rare disease can be conceived as controlled experiments of nature, in which everything is identical in the diseased and the normal organisms, except for one single factor that is the root cause of the ensuing disease. By studying the rare diseases, we can begin to piece together the more complex parts of common diseases.

The book has five large themes that emerge, in one form or another, in every chapter.

1. In the past two decades, there have been enormous advances in the diagnosis and treatment of the rare diseases. In the same period, progress in the common diseases has stagnated. Advances in the rare diseases have profoundly influenced the theory and the practice of modern medicine.

2. The molecular pathways that are operative in the rare diseases contribute to the pathogenesis of the common diseases. Hence, the rare diseases are not the exceptions to the general rules that apply to common diseases; the rare diseases are the exceptions upon which the general rules of common diseases are based.

3. Research into the genetics of common diseases indicates that these diseases are much more complex than we had anticipated. Many rare diseases have simple genetics, wherein a mutation in a single gene accounts for a clinical outcome. The same simple pathways found in the rare diseases serve as components of the common diseases. If the common diseases are the puzzles that modern medical researchers are mandated to solve, then the rare diseases are the pieces of the puzzles.

4. If we fail to study the rare diseases in a comprehensive way, we lose the opportunity to see the important biological relationships among diseases consigned to non-overlapping subdisciplines of medicine.

5. Every scientific field must have a set of fundamental principles that describes, explains, or predicts its own operation. Rare diseases operate under a set of principles, and these principles can be inferred from well documented pathologic, clinical, and epidemiologic observations.

Today, there is no recognized field of medicine devoted to the study of rare diseases; but there should be.

Content and Organization of the Book

There are three parts to the book. In Part I (Understanding the Problem), we discuss the differences between the rare and the common diseases, and why it is crucial to understand these differences. To stir your interest, here are just a few of the most striking differences: (1) most of the rare diseases occur in early childhood, while most of the common diseases occur in adulthood; (2) the genetic determinants of most rare diseases have a simple Mendelian pattern, dependent on whether the disease trait occurs in the father, or mother, or both. Genetic influences in the common diseases seldom display Mendelian inheritance; (3) rare diseases often occur as syndromes involving multiple organs through seemingly unrelated pathological processes. Common diseases usually involve a single organ or involve multiple organs involved by a common pathologic process.

The most common pathological conditions of humans are aging, metabolic diseases (including diabetes, hypertension, and obesity), diseases of the heart and vessels, infectious diseases, and cancer. Each of these disorders is characterized by pathologic processes that bear some relation to the processes that operate in rare diseases. In Part II (Rare Lessons for Common Diseases), we discuss the rare diseases that have helped us understand the common diseases. Emphasis is placed on the enormous value of rare disease research. We begin to ask and answer some of the fundamental questions raised in Part I. Specifically, how is it possible for two diseases to share the same pathologic mechanisms without sharing similar genetic alterations? Why are the common diseases often caused, in no small part, by environmental (i.e., non-genetic) influences, while the rare disease counterparts are driven by single genetic flaws? Why are the rare diseases often syndromic (i.e., involving multiple organs with multiple types of abnormalities and dysfunctions), while the so-called complex common diseases often manifest in a single pathological process? In Part II, we will discuss a variety of pathologic mechanisms that apply to classes of rare diseases. We will also see how these same mechanisms operate in the common diseases. We will explore the relationship between genotype and phenotype, and we will address one of the most important questions in modern disease biology: How is it possible that complex and variable disease genotypes operating in unique individuals will converge to produce one disease with the same biological features from individual to individual?

In Part III (Fundamental Relationships between Rare and Common Diseases), we answer the as-yet unanswered questions from Part I, plus the new questions raised in Part II. The reasons why rare diseases are different from common diseases are explained. The convergence of pathologic mechanisms and clinical outcome observed in rare diseases and common diseases, as it relates to the prevention, diagnosis, and treatment of both types of diseases, is described in detail.

The book includes a scientific rationale for funding research in the rare diseases. Currently, there is a vigorous lobbying effort, launched by coalitions of rare disease organizations, to attract research funding and donations. Funding for the rare diseases has always been small, relative to the common diseases. Funding agencies find it impractical to devote large portions of their research budget to the rare diseases, while so many people are suffering from the common diseases. As it turns out, direct funding of the common diseases has not been particularly cost effective. It is time for funders to re-evaluate their goals and priorities.

Laypersons advocating for rare disease research almost always appeal to our charitable instincts, hoping that prospective donors will respond to the plight of a few individuals. Readers will learn that such supplications are unnecessary and misdirect attention from more practical arguments. When rare diseases are funded, everyone benefits. We will see that it is much easier to find effective targeted treatments for the rare diseases than for common diseases. Furthermore, treatments that are effective against rare diseases will almost always find a place in the treatment of one or more common diseases. This assertion is not based on wishful thinking, and is not based on extrapolation from a few past triumphs wherein some treatment overlap has been found in rare and common diseases. The assertion is based on the observation that rare diseases encapsulate the many biological pathways that drive, in the aggregate, our common diseases. This simple theme is described and justified throughout the book. Society will benefit when we increase funding for the rare diseases with the primary goal of curing the common diseases. The final chapter of this book discusses promising new approaches to rare disease research.

Rules Governing the Rare Diseases

What is the value of learning a lot of facts about the rare diseases if this information cannot deepen our understanding of medicine? The genetics of human disease is incredibly complex. As we learn more and more about the human genome, we find ourselves less able to cope with all the incoming information. We need to have some way of relating intangible and invisible molecular complexities to the stark, clinical reality of human diseases. A good way to understand the complex data is by building generalizations. When we generalize, we force ourselves to think about biological relationships and their clinical consequences. Suddenly, we are no longer passive collectors of information; we become innovators, creators, and puzzle solvers. Facts that were formerly too esoteric to recall are burned into our memories as vital clues in a vast biological mystery. For the clinically minded, generalizations drive down the complexity of genetics and molecular pathology. For the research minded, generalizations are testable hypotheses; inspirational fodder for the next grant application.

The text is sprinkled with general rules that can be inferred from the chapter contents. The term rule herein means observations that are generally true; not natural laws. In many cases, counter-examples and constraints are also provided. The rules are primarily intended to encourage readers to think critically about the subject matter. Readers will find that the disease descriptions in the chapters will have greater meaning if the disease can be associated with a biological rule. Every rule appearing in the text is listed again in Appendix II, where they are numbered by chapter and section. The reader is encouraged to browse through the list. When a provocative rule is encountered, the reader can easily refer back to the chapter to read a full discussion.

Who Should Read this Book?

This book is written primarily as a text for healthcare students, professionals, and for biomedical researchers. Advocates for the rare diseases will find that this book provides a practical scientific rationale to support increased funding and new initiatives into the rare diseases and orphan drug development. For funders and administrators who have poured vast resources into genetic infrastructure, such as the Human Genome Project, they will find that the rare diseases are the bridge leading from genome databases to practical clinical innovations.

My hope is that the book will reach non-biologists working on large, multidisciplinary biomedical projects; so-called Big Science. Systems biologists, computational biologists, biomedical computer scientists, data modelers, biostatisticians, bioinformaticists, and biomedical informaticians often sit on the sidelines of biomedical research. Too often, brilliant professionals serve in complex biomedical projects without fully realizing the potential of their personal contributions. One of the purposes of this book is to provide a practical perspective of modern disease research; one that clarifies the relationships between genes, pathogenesis, and clinical phenotype.

Readers will encounter specialized terminology from the fields of genetics, pathology, microbiology, cellular physiology, and anatomy. Rather than devote chapter space to defining terms, a large glossary is provided. Glossary terms appearing for the first time within the text are labeled. In addition to defining terms, glossary items are provided with a detailed explanation of their relevance to the themes developed within the book. The glossary can be enjoyed as a stand-alone text.

How to Read this Book

Because this book attempts to establish the general biological rules that govern the rare diseases, it is necessary to provide examples of diseases to which those rules apply. This book contains descriptions of the genetic and clinical features of hundreds of rare diseases. Laypersons reading this book should take solace in knowing that the most seasoned medical professionals will be unfamiliar with many of the disease entities described herein. To facilitate the reader’s understanding of fundamental principles, I have written the book in such a way that many of the burdensome technicalities can be compartmentalized and saved for later reading after the main points of the book are absorbed. Here is how it works. The book contains about 130 biological rules, with each rule followed by a brief, non-technical rationale that explains why the rule makes sense. Rules and rationales are indented and displayed in bold font easily distinguished from the surrounding text. Each rule and rationale is followed by a detailed discussion with examples. Readers are encouraged to read through the rules, dwelling on the full discussions that have particular relevance to their own interests. Those readers who seek an in-depth treatment of the book’s subject are welcome to study the text cover to cover. In addition, the text introduces specialized terminology that may be unfamiliar to many readers. Throughout the book, short definitions of terms are provided as parenthesized comments. Terms that require in-depth explanations are discussed in the glossary. Non-biologists should not be intimidated by the highly specialized nature of the topics included here. You may need to consult a dictionary from time to time, but if you can read the science articles in The New York Times, then you will be able to read and understand every chapter in this book.

Chapter 1

What are the Rare Diseases, and Why do we Care?

Abstract

In the U.S., rare diseases are disorders that affect fewer than 200,000 individuals. There are about 7000 known rare diseases affecting, in aggregate, 25–30 million Americans. Many of the rare diseases are caused by single gene mutations, often occurring as inherited diseases with a simple Mendelian pattern of inheritance. In the past few decades, most of the scientific breakthroughs in disease research have come from research in the rare diseases. No such comparable progress has occurred in the area of the common diseases.

Keywords

Rare Diseases Act of 2002; Number of rare diseases; Incidence of rare diseases; Definition of rare diseases; Orphan diseases

1.1 The definition of rare disease

The beginnings and endings of all human undertakings are untidy.

—John Galsworthy

In the U.S., Public Law 107-280, the Rare Diseases Act of 2002 states: Rare diseases and disorders are those which affect small patient populations, typically populations smaller than 200,000 individuals in the United States [1]. Since the population of the U.S. is about 314 million (in 2013), this comes to about one case for every 1570 persons. This is not too far from the definition recommended by the European Commission on Public Health; fewer than one in 2000 people. It is important to have numeric criteria for the rare diseases, because special laws exist in the U.S. and in Europe to stimulate research and drug development for diseases that meet the criteria for being rare (see Section 14.2). Unfortunately, it is very difficult to know, with any certainty, the specific prevalence or incidence of any of the rare diseases (see Glossary items, Prevalence, Incidence). A certain percentage of the cases will go unreported, or undiagnosed, or misdiagnosed. Though it is impossible to obtain accurate and up-to-date prevalence data on every rare disease, in the U.S. the National Institutes of Health has estimated that rare diseases affect, in aggregate, 25–30 million Americans [2].

There seems to be a growing consensus that there are about 7000 rare diseases [3]. Depending on how you choose to count diseases, this may be a gross underestimate. There are several thousand inherited conditions with a Mendelian inheritance pattern [4]. To these, we must add the different types of cancer. Every cancer, other than the top five or ten most common cancers, occurs with an incidence much less than 200,000 and would qualify as a rare disease. There are more than 3000 named types of cancer, and many of these cancers have well-defined subtypes, with their own morphologic, clinical, or genetic characteristics. Including defined subtypes, there are well over 6000 rare types of cancer [5–8]. Regarding the rare infectious diseases, well over 1400 different infectious organisms have been reported in the literature [9]. A single infectious organism may manifest as several different named conditions, each with its own distinctive clinical features. For example, leishmaniasis, an infectious disease that is common in Africa but rare in Europe, may present in one of four different forms (cutaneous, visceral, diffuse cutaneous, and mucocutaneous). When we add in the many rare nutritional, toxic, and degenerative diseases that occur in humans, the consensus estimate of the number of rare diseases seems woefully inadequate. Nonetheless, the low-ball 7000 number tells us that there are many rare diseases; way too many for any individual to fully comprehend.

The rare diseases are sometimes referred to as orphan diseases. The term is apt for several reasons. First, the term orphan applies to children, and it happens that neonates, infants, and children are at highest risk for the most devastating rare diseases. Second, the concept of an orphan disease implies a lack of stewardship. For far too long, the rare diseases were neglected by clinicians, medical researchers, the pharmaceutical industry, and society in general (see Glossary item, Neglected disease). The rare diseases manifested as strange and often disfiguring maladies that occurred without any obvious cause. Primitive and not-so-primitive cultures have attributed a supernatural origin for the rare diseases of childhood. It was common for children with disfiguring diseases to be confined in homes or institutions and hidden from society. Over the past 40 years, these conditions have changed drastically, and for the better. A confluence of political, social, and scientific enlightenments has led to stunning advances in the field of rare diseases, and these advances have spilled over into the common diseases. If the rare diseases are orphans, then orphans have been adopted by caring and competent guardians.

Today, there are effective treatments for many of the rare diseases. Hence, it is crucial to make correct diagnoses, at early stages of disease, before irreversible organ damage develops.

1.1.1 Rule—Rare diseases are easily misdiagnosed, and are often mistaken for a common disease or for some other rare disease.

Brief Rationale—It is impossible for any physician to attain clinical experience with more than a small fraction of the total number of rare diseases. When it comes to rare diseases, every doctor is a dilettante.

In 1993, Reggie Lewis was the 27-year-old captain of the Boston Celtics basketball team. Mr. Lewis enjoyed good health until the moment when he collapsed during a basketball game. Mr. Lewis’ collapse attracted the attention of cardiologists across the nation. A medical team assembled by the New England Baptist Hospital opined that Mr. Lewis had cardiomyopathy, a life-threatening condition that would require Mr. Lewis to retire from basketball immediately. A second team of experts, assembled at the Brigham and Women’s Hospital, disagreed. They rendered a diagnosis of vaso-vagal fainting, a benign condition. A third team of experts, from St. John’s Hospital in Santa Monica, California, was non-committal. The Santa Monica team suggested that Mr. Lewis play basketball, but with a heart monitor attached to his body. With three discordant diagnoses, Mr. Lewis decided to take his chances, continuing his athletic career. Soon thereafter, Lewis died, quite suddenly, from cardiomyopathy, while playing basketball [10].

A few dozen common diseases account for the majority of ailments encountered in the typical medical practice. When a physician encounters a rare disease for the first time, he or she may be no more capable than a medical student to reach a correct diagnosis. The presenting symptoms of many rare diseases are disarmingly pedestrian (e.g., failure to thrive, weakness, fatigability, etc.) and the first reaction of any physician might be to make a tentative diagnosis of a common disease. Only after treatment fails, and symptoms do not resolve, are alternate diagnoses considered. It is not unusual for an accurate diagnosis to follow numerous visits to several physicians [11]. In the interim, the disease worsens, the medical bills grow, and the emotional distress builds.

1.2 Remarkable progress in the rare diseases

Most [rare diseases] result from a dysfunction of a single pathway due to a defective gene. Understanding the impact of a single defect may therefore yield insights into the more complex pathways involved in common diseases which are generally multifactorial.

—Segolene Ayme and Virginie Hivert, from Orphanet [12].

Excluding genes causing rare cancers, more than 2000 genes have been linked to 2000 rare diseases [12]. In most cases, these links are presumed to be causal (i.e., mutations in the gene lead to the development of the disease). Virtually every gene known to cause a rare disease was discovered within the past half century. The diseases whose underlying causes were known, prior to about 1960, numbered in the hundreds, and the majority of these well-understood diseases were caused by infectious organisms (see Glossary item, Infectious disease).

Progress in the genetic diseases greatly accelerated in the 1960s, and the earliest advances came to the group of diseases known as inborn errors of metabolism. Treatments consisted of avoidance of substances that could not be metabolized in affected individuals or supplementations for missing metabolites (e.g., avoidance of phenylalanine in newborns with phenylketonuria, supplements of thyroid hormone in congenital hypothyroidism, avoidance of galactose in newborns with galactosemia, supplementation with biotin in newborns with biotinidase deficiency, specially formulated low protein diets for newborns with maple syrup urine disease, and so on).

Some of the groundbreaking advances in rare disease research include the 1956 discovery of the specific molecular alteration in hemoglobin that causes sickle cell disease [13,14]; and the identification of the cystic fibrosis gene in 1989 [15]. In 2007, Leber congenital amaurosis, a form of inherited blindness, was the first disease to be treated, with some clinical improvement, using genetic engineering. The mutated RPE65 gene was replaced with a functioning gene [16]. Partial vision was obtained in individuals who were previously blind. It remains to be seen whether genetic engineering will ever restore adequate and long-term vision to individuals with Leber congenital amaurosis [17]. It is noteworthy that the test case was made on an extremely rare form of blindness, not a common form such as macular degeneration. The reason why rare diseases are superior to common diseases, when developing innovative treatment methods, is a topic that will be discussed in Chapter 14.

Currently, drug development for the rare diseases is far exceeding anything seen in the common diseases. Since 1983, more than 350 drugs have been approved to treat rare diseases [18]. By 2011, the U.S. Food and Drug Administration had designated over 2300 medicines as orphan drugs (see Glossary item, Orphan drug). That same year, 460 drugs were in development to treat or prevent the rare diseases [18]. Meanwhile, in Europe, 20% of the innovative products with marketing authorization were developed for rare diseases [12].

As we shall discuss in later chapters, many factors have contributed to the remarkable advances in the rare diseases. The upshot of these advances is that we know much more about the rare diseases, in terms of pathogenesis and treatment, than we know about the common diseases (see Glossary item, Pathogenesis). At this point, there is every expectation that the greatest breakthroughs in understanding the general mechanisms of disease processes will come from research on the rare diseases [19].

Let us briefly examine a few general statements that will be developed in ensuing chapters.

1.2.1 Rule—Rare diseases are not the exceptions to the general rules of disease biology; they are the exceptions upon which the general rules are based.

Brief Rationale—All biological systems must follow the same rules. If a rare disease is the basis for a general assertion about the biology of disease, then the rule must apply to the common diseases.

Every rare disease tells us something about the normal functions of organisms. When we study a rare hemoglobinopathy, we learn something about the consequences that befall when normal hemoglobin is replaced with an abnormal hemoglobin. This information leads us to a deeper understanding of the normal role of hemoglobin. Likewise, rare urea cycle disorders, coagulation disorders, metabolic disorders, and endocrine disorders have taught us how these functional pathways operate under normal conditions (see Glossary item, Pathway) [19].

1.2.2 Rule—Every common disease is a collection of different diseases that happen to have the same clinical phenotype (see Glossary item, Phenotype).

Brief Rationale—Numerous causes and pathways may lead to the same biological outcome.

Consider the heart attack; its risk of occurrence is elevated by many factors. Obesity, poor diet, smoking, stress, lack of exercise, hypertension, diabetes, disorders of blood lipid metabolism, infections, male gender; they all contribute to heart attacks. Regardless of the contributing factors, a common event precedes and causes the heart attack; the blockage of a coronary artery. Blockage is often caused by an atherosclerotic plaque. Consequently, rare inherited conditions that produce atherosclerotic plaques can produce the common heart attack (e.g., inherited disorders of lipid metabolism). We infer that for every common disease, there are rare, inherited diseases that account for a small subset of cases. This topic will be revisited and expanded in Section 12.2.

1.2.3 Rule—Rare diseases inform us how to treat common diseases.

Brief Rationale—When we encounter a common disease, we look to see what pathways are dysfunctional, and we develop a rational approach to prevention, diagnosis, and treatment based on experiences drawn from the rare diseases that are driven by the same dysfunctional pathways.

Many heart attacks are caused by atherosclerotic plaque blocking a coronary artery. Many conditions produce atherosclerotic plaque, but a rare condition known as familial hypercholesterolemia is associated with some cases of coronary atherosclerosis that occur in young individuals. Studies on familial hypercholesterolemia led to the finding that statins inhibit the rate-limiting enzyme in cholesterol synthesis (hydroxymethylglutaryl coenzyme A), thus reducing the blood levels of cholesterol and blocking the formation of plaque. The treatment of a pathway operative in a rare form of hypercholesterolemia has become the most effective treatment for commonly occurring forms of hypercholesterolemia, and a mainstay in the prevention of the common heart attack [20]. This topic will be revisited and expanded in Section 13.2.

References

1. Rare Diseases Act of 2002, Public Law 107-280, 107th U.S. Congress, November 6, 2002.

2. FAQ About Rare Diseases. National Center for Advancing Translational Sciences, National Institutes of Health. http://www.ncats.nih.gov/about/faq/rare/rare-faq.html, viewed on October 24, 2013.

3. M.J. Field, T. Boat, Rare diseases and orphan products: accelerating research and development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development, 2010. The National Academies Press, Washington, DC. Available from: http://www.ncbi.nlm.nih.gov/books/NBK56189/.

4. OMIM. Online Mendelian Inheritance in Man. Available from: http://omim.org/downloads, viewed June 20, 2013.

5. Berman JJ. Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches. BMC Cancer. 2005;5:100 Available from: http://www.biomedcentral.com/1471-2407/5/100.

6. Berman JJ. Tumor taxonomy for the developmental lineage classification of neoplasms. BMC Cancer. 2004;4:88.

7. Berman JJ. Tumor classification: molecular analysis meets Aristotle. BMC Cancer. 2004;4:10 Available from: http://www.biomedcentral.com/1471-2407/4/10.

8. Berman JJ. Neoplasms: Principles of Development and Diversity. Sudbury: Jones & Bartlett; 2009.

9. Berman JJ. Taxonomic Guide to Infections Diseases: Understanding the Biologic Classes of Pathogenic Organisms. Waltham: Academic Press; 2012.

10. Altman LK. After a highly publicized death, second-guessing second opinions. The New York Times, August 3, 1993.

11. Rare Diseases and Scientific Inquiry. Developed by BSCS Under a Contract from the National Institutes of Health, Office of Rare Diseases Research, 2011.

12. Ayme S, Hivert V, eds. Report on Rare Disease Research its Determinants in Europe and the Way Forward. INSERM May 2011; Available from: http://asso.orpha.net/RDPlatform/upload/file/RDPlatform_final_report.pdf, viewed February 26, 2013.

13. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949;110:543–548.

14. Ingram VM. A specific chemical difference between globins of normal and sickle-cell anemia hemoglobins. Nature. 1956;178:792–794.

15. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–1073.

16. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19:979–990.

17. Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci USA. 2013;110:E517–E525.

18. Orphan Drugs in Development for Rare Diseases. 2011 Report. America’s Biopharmaceutical Research Companies. Available from: http://www.phrma.org/sites/default/files/pdf/rarediseases2011.pdf, viewed July 14, 2013.

19. Wizemann T, Robinson S, Giffin R. Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies Workshop Summary. National Academy of Sciences, 2009.

20. Stossel TP. The discovery of statins. Cell. 2008;134:903–905.

Chapter 2

What are the Common Diseases?

Abstract

Pareto’s principle, also known as the 80/20 rule, holds that a small number of items account for the vast majority of observations. For example, a small number of rich people account for the majority of wealth. Diseases follow Pareto’s principle in that a very small number of common diseases account for the majority of morbidity and mortality worldwide. For decades, the assumption has been that funding should be targeted to the small number of diseases that cause the greatest damage to our health. This blunt approach has not worked well. The common diseases have proven themselves to be much too complex and clinically heterogeneous for simple analysis. This chapter introduces the idea that progress against the common diseases will need to follow progress in the rare diseases.

Keywords

Pareto’s principle; Zipf distribution; Heart disease; Cancer; Hypertension; Diabetes; Obesity; Metabolic diseases; Infectious diseases

2.1 The common diseases of humans, a short but terrifying list

Not everything that counts can be counted, and not everything that can be counted counts.

—William Bruce Cameron

There are about 7 billion humans living in the world today, with about 57 million people dying each year [1,2]. There are about 312 million persons residing in the U.S. [3,1]. The U.S. Central Intelligence Agency estimates that U.S. crude death rate is 8.36 per 1000 and the world crude death rate is 8.12 per 1000 [4]. This translates to 2.6 million people dying in 2011 in the U.S. These figures are just a tad higher than the total U.S. deaths calculated independently from the 2003 National Vital Statistics Report [5]. Authoritative death statistics correlate surprisingly well with the widely used rule of thumb that 1% of the human population dies every year. What diseases account for all of these deaths?

Let us take a look at diseases that cause the greatest number of human deaths worldwide.

Worldwide deaths in 2008, from the World Health Organization [2]:

U.S. deaths in 2003, from National Vital Statistics Report [5]:

There is much to be learned from these two short lists. We see that although there are thousands of human diseases, many of which are capable of causing death, only a few diseases account for the bulk of death occurring in populations. For both U.S. deaths and worldwide deaths, the first three conditions on each list account for more than 50% of the total number of deaths. The top seven conditions account for 70% of the total number of deaths worldwide.

2.1.1 Rule—A small number of diseases account for most instances of morbidity or mortality.

Brief Rationale—Pareto’s principle applies to biological systems.

Pareto’s principle, also known as the 80/20 rule, holds that a small number of causes will account for the vast majority of observed instances of real-world distributions (see Glossary item, Pareto’s principle). For example, a small number of rich people account for the majority of wealth. A few troublemakers in a classroom may draw the bulk of a teacher’s attention. Just two countries, India and China, account for 37% of the world population. Within most countries, a small number of provinces or geographic areas contain the majority of the population of a country (e.g., east and