DISEASE COMPLEXITY: RARE DISEASES AND COMMON DISEASES

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

In most cases, rare genetic diseases are produced by a single mutation in a single gene, to produce a rare disease that typically develops early in life, often with a rather uniform clinical presentation. In Chapter 7, some of the complexities of single-gene disorders are discussed. Here is an excerpt:

A single gene may produce a protein product whose function varies depending on the specific site and type of mutation in the gene. Hence, variations in a gene can produce different diseases. For example, different mutations of the same gene, desmoplakin, cause the following diseases:

- Arrhythmogenic right ventricular dysplasia-8

- Dilated cardiomyopathy with woolly hair and keratoderma

- Lethal acantholytic epidermolysis bullosa

- Keratosis palmoplantaris striata II

- Skin fragility-woolly hair syndrome

In some cases, variation in the sites of mutations in a gene does not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott–Aldrich syndrome, discussed in Section 7.1, mutations that truncate the protein product of the WAS gene will produce severe disease, while mutations that produce changes in single amino acids, without changing the length of the protein, will tend to produce mild disease [14].

In other cases, the [epigenetic] gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, the H19 differentially methylated region is a site on chromosome 11p15.5 in which microdeletions occur in some cases of Beckwith–Wiedemann syndrome and Russell–Silver syndrome. Opposite methylation patterns in the H19 differentially methylated region will cause Beckwith–Wiedemann syndrome when there is gain-of-methylation and Russell–Silver syndrome when there is loss-of-methylation (see Glossary item, Gain-of-function) [15]. Beckwith–Wiedemann syndrome is characterized by tissue overgrowth and tumor formation [16]. Russell–Silver syndrome is characterized by dwarfism. The role of methylation in epigenetic regulation will be described in further detail in Chapter 10.

If single-gene disorders can be complex, try to imagine the biological complexity of common diseases, which typically have a polygenic origin (i.e., multiple genes involved), with multiple environmental influences, with symptoms developing in steps, sometimes extending over decades! The difficulty understanding the biology of the common diseases, in contrast with the relative ease of understanding the rare diseases, is a topic that is explored in depth in the book.

I urge you to read more about this book. There's a good preview of the book at the Google Books site.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, disease complexity, complex diseases, genetics of disease, monogenic disease, polygenic disease, orphan disease, orphan drugs, Beckwith-Wiedemann, Wiskott-Aldrich

Case Reports of Rare Diseases Have General Value

The Case Report (also known as Case Study) is a poorly utilized resource. Every healthcare worker is familiar with case reports; medical journals sometimes contain a section devoted to them. Case reports typically begin with a comment regarding the extreme rarity of the featured disease. You can expect to see phrases such as "fewer than a dozen have been reported in the literature" or "the authors have encountered no other cases of this lesion," or such and such a finding makes this lesion particularly uncommon and difficult to diagnose; and so on. The point that the authors are trying to convey is that the case report is worthy of publication specifically because it is rare. After describing the clinical and pathologic features of the case, there is usually some obligatory paragraph explaining how the disease can be distinguished from more common diseases, with which it may have overlapping clinical or pathological features. Sometimes the case report will contain an end-paragraph that undermines the accuracy of the start-paragraph, suggesting that the lesion is more common than one might think; implying here that under-diagnosis is the root cause of the lesion's apparent rarity. Always, the case report serves as a cautionary exercise, intended to ward against misdiagnosis.

The "beware this lesion" approach to case reporting can easily miss the most important aspect of this type of publication. Science, and most aspects of human understanding, involve generalizing from the specific. When Isaac Newton saw an apple falling, he was not thinking that he could write a case report about how he once saw an apple drop, thus warning others not to stand under apple trees lest a rare apple might thump them upon the head. Newton generalized from the apple to all objects, and questioned the basic nature of gravity, to produce mathematically-described laws by which gravity interacts with matter.

Every case report of a rare disease or of a rare presentation of a common disease should serve as a special instance of a general phenomenon. In natural systems, there are no outliers. Every event, no matter how rare, is produced as the consequence of general laws of nature. The case report gives us an opportunity to clarify the general way things work, by isolating one specific and rarely observed factor.

Here is an example.

The common heart attack is 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.

In this case, the rare instances of inherited hypercholesterolemia clarified the general pathway leading to atherogenesis. Yes, when first encountered, inherited hypercholesterolemia is just the kind of disease that might have appeared as a case report. It would have been a terrible injustice for such a case to be treated merely as a curiosity of medicine or as a cautionary tale for medical students.

The process by which observations on rare diseases can be applied generally to all diseases, is discussed in detail in my recently published book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site.

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

tags: case report, case study, rare diseases, orphan diseases, orphan drugs, generalizing from rare to common, what is the purpose of case reports, case reporting, case studies, heart attack, heart disease, cholesterol

When Rare Diseases and Common Diseases Converge to the Same Clinical Picture

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

In yesterday's blog, we discussed by a rare disease and a common disease may both have the same clinical presentation, a phenomenon that I call disease convergence. The short explanation for disease convergence is that there are a limited number of ways that the body can respond to malfunctions.

Here is an excerpt from Chapter 10, in which disease convergence is discussed:

Hypertension is another excellent example of convergence toward a common phenotype. As discussed in Section 5.4, there are numerous genetic and environmental causes of hypertension. The causes of hypertension may include overactivity of the renin–angiotensin system, or channel defects at various sites of the renal tubule, or arterial wall pathology, or increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease converge onto one physiologic pathway: increased net salt balance leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure [8]. Regardless of the underlying mechanism leading to an individual’s hypertension, diuretics such as hydrochlorothiazide or furosemide, which reduce the reabsorption of sodium in the kidneys, will almost always lower blood pressure. We see a similar phenomenon with rare and common causes of diabetes. Extremely rare single gene diabetes, including HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, is controlled with sulfonylurea, the same drug used to treat common type 2 diabetes. The cause of monogenic diabetes is quite different from the cause of common type 2 diabetes, but their pathways converge; and all these diseases respond to the same treatment [9].

Some of the rare diseases exhibit convergence with one another. For example, epidermolysis bullosa is an inherited disease characterized by blistering of the skin and mucosal membranes (e.g., mouth). It is always caused by a defect in the mechanism whereby the epidermis is anchored onto the underlying dermis. Blisters are formed in locations where the epidermis lifts off the dermis, usually at sites of friction. Over 300 gene defects can result in epidermolysis bullosa. Depending on the variant form of the disease, any of several different genes may serve as the underlying cause (e.g., COL, PLEC, Desmoplakin genes). There is also an autoimmune form of epidermolysis bullosa acquisita, wherein antibodies target Type VII collagen, a component of the basement membrane glue that lies between the epidermis and the dermis. Regardless of the underlying cause, all variants of epidermolysis bullosa converge to a blistering phenotype.

10.1.3 Rule—A large set of cellular defects accounts for a relatively small number of possible pathologic conditions. Brief Rationale—In any complex system, there are a limited number of functional parts, but each functional part can break down due to a vast number of possible defects.

We can see that nothing in the universe is ever as chaotic as we might expect from the complexity of the individual elements of the system. Despite the enormous number of atoms in the universe, there seem to be just a few dozen types of cosmological bodies (e.g., stars, planets, black holes). These bodies assemble into galaxies that seem to have a relatively narrow array of shapes and sizes. In the case of biological systems, complex processes settle for a limited number of outcome categories.

10.1.4 Rule—Regardless of the complexity of a system, the outcomes are typically repeatable and stable.
Brief Rationale—All existing biological systems, despite their complexity, converge toward stability. If a biological system were unstable, it would cease to exist.

The phenomenon of convergence may explain some of the genetic complexity that seems to characterize many, if not all, of the common diseases. When there are hundreds or thousands of gene variations that are associated with one disease, it is likely that all these different genes contribute to a limited range of available disease pathways. In diseases that have a complex genetic etiology, it makes sense to examine the pathways that converge to a final clinical phenotype, rather than to try to understand the individual contribution from each variant gene.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.

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

tags: convergence, disease convergence, orphan diseases, orphan drugs, drug development, common diseases, complex diseases, rare disease models of common diseases, disease pathway, complex diseases, common diseases, disease phenotype, pathogenesis, disease pathway

Rare Diseases and Common Diseases can Converge to the Same Clinical Conditions

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is a short excerpt from Chapter 10.

As applied to diseases, convergence occurs when different genes, cellular events, exposures, and pathogenetic mechanisms all lead to a similar clinical phenotype. Convergence is found in common diseases and in rare diseases. In the case of systemic responses to injury, convergence may have an evolutionary origin. For example, humans have evolved to respond in an orchestrated way to a variety of pathologic stimuli. Various antigens can stimulate an orchestrated acute allergic response that may be identical for a wide variety of antigens (hives, bronchial constriction, puffy eyes). Likewise, humans have evolved to a systemic response to local infection that is specific for our species [7]. Convergence is observed in all the rare diseases that have genetic heterogeneity, either allelic heterogeneity or locus heterogeneity (see Section 9.3). In these cases, many underlying genetic causes yield the same clinical phenotype.

10.1.2 Rule—Regardless of the path taken, many pathologic processes will converge to the same pathologic condition.
Brief Rationale—There are a limited number of ways that the body can respond to malfunctions.

Think about all the things that can go wrong with your car. The engine can stop, the fuel system can be interrupted, the battery may die, the brakes may fail, any of the four tires can flatten, the headlights may not work, the electrical system may suffer a circuit shortage, and so on. It seems like a long list, but it is not. Maybe a dozen common problems account for the vast majority of car problems. Add these to a few dozen less likely problems, and you have a listing that would cover 99% of automobile repair issues. Every auto repairman knows that there are a limited number of systems in the car that can go bad. Repairs are relatively easy if the repairman can determine the system or part that is at fault. Whereas the number of different auto problems is limited, the number of events that can lead to these problems is virtually infinite. An auto repairman knows that for every engine breakdown, there might be thousands of possible causes. A non-functioning engine can be corrected by taking out the bad engine and putting in a new engine. If he is a very good repairman, he will determine whether a problem in a different system (e.g., the fuel injector) was indirectly responsible for the engine failure. Diagnostic tools should determine when a defect in one system is responsible for a defect in another system. Humans, like automobiles, are highly complex. Nonetheless, there are a limited number of problems that can occur in a complex organism. Heart attacks exemplify pathological convergence. Many different pathological processes can lead to the blockage of a coronary artery, such as: atherosclerotic plaque, hypertrophy of the arterial wall, spasms of the artery, acute infection of the artery, thrombus formation within the artery, arterial tear or dissection, developmental defects resulting in narrowing. Genes and environment contribute to these mechanisms. In the end, they can all produce one clinical phenotype; the all-too-common heart attack.

In chapter 10, we explore disease convergence, and explain why rare diseases and common diseases may sometimes converge to the same clinical phenotype. In many cases, treatments developed for a rare disease will be effective against a common disease that shares its convergent pathway (example, rare causes of hypertension and common causes of hypertension all responding to to the same treatment regimens).

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.

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

tags: rare disease, rare disease research, rare diseases, orphan diseases, orphan drugs, drug development, common diseases, complex diseases, rare disease models of common diseases

Rare Disease Legislation in the U.S.

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is a short excerpt from Chapter 14.

Many countries have passed legislation ensuring that the rare diseases receive research funding, that pharmaceutical companies are encouraged to produce medications for the rare diseases, and that individuals and families receive necessary medical and emotional support. In the U.S., some of the most important political milestones have been the following:

- Public Law 97-414, the Orphan Drug Act of 1983 defines rare diseases and provides sponsors of drugs intended to treat rare diseases with protection from competition (i.e., 7 years of market exclusivity), tax credits, and various other incentives.

- Public Law 101-629, the Safe Medical Devices Act of 1990 provides incentives and exemptions for devices, much as prior legislation covered drugs. The Act applies to devices to treat or diagnose diseases affecting fewer than 4000 individuals [3].

- Public Law 105-115, the FDA Modernization Act of 1997 grants an exemption for orphan drugs from drug approval application fees that would otherwise apply [3]. Amendments to the Act in 2007 include the Best Pharmaceuticals for Children Act (Public Law 110-85), which encourages the recruitment of children into clinical trials.

- Public Law 107-280, the Rare Diseases Act of 2002 directed the National Institutes of Health (NIH) to establish an Office of Rare Diseases and, through this office, to support regional centers of excellence or clinical research into the rare diseases [4]. The Act also increased funding for the development of diagnostics and treatments for the rare diseases [5].

- Public Law 108-155, the Pediatric Research Equity Act of 2003 is a somewhat ambivalent law that requires applications for new drugs to test for safety and effectiveness in relevant pediatric populations, while providing full and partial waivers from the law when such testing is considered impractical.

- Public Law 110-233, the Genetic Information Nondiscrimination Act of 2008 makes it illegal to discriminate against employees or applicants for employment based on their personal genetic information (i.e., whether individuals or family members have a genetic disease or condition, or whether individuals are at risk of developing a disease or condition based on genetic testing).

- Public Law 111-80, the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 authorized the FDA to appoint a review group to recommend design improvements for preclinical and clinical trials aimed at preventing, diagnosing, and treating rare diseases [3].

- Public Law 111-148, the Patient Protection and Affordable Care Act of 2010, known widely as ObamaCare requires insurance companies to cover all applicants regardless of pre-existing conditions. As generally interpreted, the Act will eliminate lifetime caps on benefits.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: rare disease legislation, rare disease laws, u.s. support for rare diseases, rare disease research, rare diseases, orphan diseases, orphan drugs, fda, drug development

Definition of Rare Disease

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Short excerpt from the Introduction chapter:

“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.

Later chapters explain that the rare diseases, as a group, share a common set of biological properties that distinguish them from the common diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: rare diseases, orphan drugs, orphan diseases, common diseases, definition of rare diseases, rare disease organizations, organizations for rare diseases, rare disease research

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Chapter 13 describes the diagnostic methods, for common diseases, that have come, and will continue to come, from research into the rare diseases.

In former times, the sole purpose of diagnostics was to apply a name of a disease to a clinical condition. If the name was known, a treatment could be applied. If no treatment was available, there was always prayer. Today, it is not sufficient to simply provide a name for a disease. Diagnosis today covers a wide range of activities, including:

-Risk prediction—Determining whether an individual is at increased risk of developing a disease at some unspecified future time.

-Screening—Determining whether an individual falls into a separable group of individuals who are likely to have the disease at the time of screening. After screening, further studies would be necessary to determine whether the individual actually has the disease.

-Early detection—Determining whether an individual has a disease at an early stage of development. Early detection is often confused with disease screening. Early detection determines whether an individual has the disease at an early, usually pre-clinical, stage. Screening (see above) determines whether an individual is likely to have the disease.

-Molecular diagnosis—Determining the presence of disease with a molecular technique performed on very small samples of tissues. Molecular diagnosis typically replaces, supplements, or confirms traditional diagnostic methods, such as surgical biopsy.

-Subtyping—Determining which biological subtype of disease applies to an individual.

-Response prediction—Determining whether an individual with a disease is likely to respond to a particular treatment.

-Staging—Determining the extent to which a disease has advanced within an individual.

-Surveillance for minimal residual disease and for recurrence. The objective of minimal residual disease surveillance is to determine whether there are any traces of disease, not observable by standard clinical examination, that persist following treatment. The objective of recurrence surveillance is to determine whether a disease has recurred after remission.

When we review these various new diagnostic activities, we see that they recapitulate the steps of disease pathogenesis: the conditions that place an individual at risk of developing disease, the earliest steps in pathogenesis, the development of precursor lesions, response pathways, and disease progression. New laboratory tests are designed to measure markers for the genes and pathways that account for the components of pathogenesis.

Chapter 13 explains that the genes and pathways that lead to rare diseases are the pathogenetic building blocks of common diseases. Hence, the diagnostic techniques applied to a common disease will likely draw on knowledge obtained from one or more rare diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: complex diagnoses, clinical pathology, biomarkers, new biomarkers, molecular tests, rare diseases, orphan drugs, orphan diseases

Rare Diseases Account for Subsets of Common Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

One of the key messages of the book is that common diseases are complex, with multiple causes, lots of associated gene variations, many different aberrant pathways, and affecting heterogeneous populations (e.g., subsets of people who seem to have clinically distinctive forms of the same disease, or subsets of people who respond quite differently to the same treatment).

Contrariwise, rare diseases are usually simple: one cause, one responsible gene, one aberrant pathway, often strikingly uniform clinical features.

In Chapter 12, I build the case that particular subsets of the common diseases can often be accounted for by rare diseases. Rare diseases that account for subsets of common diseases typically have a monogenic cause, and occur at a young age (as we see in most other rare diseases). An example would be midline lung cancer of the young, a rare subset of lung cancer caused by a mutation in the NUT gene.

Here is an excerpt from Chapter 12, in which rare diseases accounting for subsets of some of the common diseases, are listed:

- MODY (maturity onset diabetes of the young), also known as monogenic diabetes, refers to any of several hereditary forms of the disease. Despite its name, MODY has a childhood onset, like most other rare diseases. The “maturity onset” in its name refers to its common disease counterpart.

- Fragile X syndrome (FXS), also known as Martin–Bell syndrome, is a monogenic cause of autism.

- McKusick–Kaufman syndrome and Bardet–Biedl syndrome-6 are both diseases that include a monogenic form that causes obesity.

- Monogenic emphysema due to alpha-1-antitrypsin deficiency [32].

- Monogenic gallstone disease due to a mutation in the ABCB4 gene.

- Monogenic cardiomyopathy due to a mutation in the ABCC9 gene.

- Monogenic cardiac arrhythmia due to monogenic mutations in ion channel genes (see Section 5.3).

- Monogenic cause of migraine in familial hemiplegic migraine type 2 and familial basilar migraine due to mutations in the gene encoding the alpha-2 subunit of the sodium/potassium pump.

- Monogenic osteoarthritis, as a component of familial osteochondritis dissecans, due to mutation in the ACAN gene.

- Familial Alzheimer disease type 1 due to a mutation in the gene encoding the amyloid precursor protein.

- Monogenic, Mendelian forms of hypertension associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules (see Section 5.4 for detailed discussion). Changes in electrolyte transport result in increased retention of sodium and to an increased volume of body fluid [33–35].

- Autoinflammatory syndromes with monogenic subtypes, including familial Mediterranean fever caused by a mutation in the MEFV gene encoding pyrin [36]."

These, and many other examples discussed in my book, indicate that if the common diseases are puzzles, then the rare diseases are the pieces of the puzzle.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

Improving Clinical Trials by Focusing on Rare Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

In Chapter 14, the importance of rare disease research in the design and execution of clinical trials is discussed. Here is an excerpt from the chapter.:

It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed toadvance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.

14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.

Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].

14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases.

Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are much more homogeneous than the common diseases, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.

Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

End of Chapter 14 excerpt.

Other chapters in my book explain why the common diseases share the same biological pathways that operate in the rare diseases; hence, drugs effective against the rare diseases will find application in the treatment of the common diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: clinical trials, orphan drugs, drug trials, rare diseases, zebra diseases, rare disease organizations, rare disease advocates, cancer trials, diabetes trials, clinical trials for common diseases, clinical trials for rare diseases, rare diseases and orphan drugs, accrual

Rare Diseases of Unknown Origin

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. This book builds the case that the best way to advance our understanding of the common diseases is to focus our attention on the rare diseases.

Here is a short excerpt from Chapter 6:

There are a number of rare diseases of unknown etiology. Some of these diseases may be caused by infectious agents.

6.4.1 Rule—A portion of human diseases of unknown etiology will eventually be shown to have an infectious etiology.

Brief Rationale—It is difficult to satisfy Koch’s postulates for every type of infectious disease (see Glossary item, Koch’s postulates). Nonetheless, if efforts to find a non-infectious cause of a disease fail, and if the temporal and geographic pattern of disease occurrences resembles the typical pattern of an infectious epidemic, then an infectious etiology is likely.

Here is an incomplete list of the rare or uncommon diseases whose etiologies are unknown:

Acrocyanosis
Balanitis xerotica obliterans
Behçet disease
Benign fasciculation syndrome
Brainerd diarrhea
Cardiac syndrome X
Chronic fatigue syndrome
Chronic prostatitis/chronic pelvic pain syndrome
Chronic Kidney Disease of unknown causes (in Central America)
Cluster headache
Complex regional pain syndrome
Copenhagen disease
Cronkhite–Canada syndrome
Cyclic vomiting syndrome
Dancing mania
Dancing plague of 1518
Danubian endemic familial nephropathy
Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome)
Electromagnetic hypersensitivity
Encephalitis lethargica
Exploding head syndrome
Fibromyalgia
Fields’ disease
Functional colonic disease
Giant cell (temporal) arteritis
Gluten-sensitive idiopathic neuropathies
Gorham vanishing bone disease
Granuloma annulare
Granulomatosis with polyangiitis (Wegener’s syndrome)
Gulf War syndrome
Hallermann–Streiff syndrome
Heavy legs
Henoch–Schönlein purpura
Interstitial cystitis
Irritable bowel syndrome
Kawasaki disease
Lichen sclerosus
Lytico–Bodig disease
Microscopic polyangiitis
Morgellons disease
Mortimer’s disease
Myofascial pain syndrome
New daily persistent headache
Nodding disease
Peruvian meteorite illness of 2007
Picardy sweat
Pigmented villonodular synovitis
Pityriasis rosea
Polyarteritis nodosa
Posterior cortical atrophy
Prurigo nodularis
SAPHO syndrome
Sarcoidosis
Sick building syndrome
Sjögren’s syndrome
Spontaneous cerebrospinal fluid leak
Stiff person syndrome
Sudden unexpected death syndrome (some cases)
Sweating sickness
Synovial osteochondromatosis
Takayasu’s arteritis
Tolosa–Hunt syndrome
Torticollis
Trichodynia
Trigger finger
Tropical sprue

Based on past experience, we can infer that some portion of the diseases of unknown etiology will have an infectious etiology. Whipple disease, previously a disease of unknown etiology, is characterized by organ infiltrations by foamy macrophages (i.e., scavenger cells that “eat” bacteria and debris). The organ most often compromised is the small intestine, where infiltration of infected macrophages in the lamina propria (i.e., a strip of connective tissue subjacent to the epithelial lining of the small intestine) causes malabsorption. Whipple disease is rare. It occurs most often in farmers and gardeners who work with soil. Whipple disease was first described in 1907 [35], but its cause was unknown until 1992, when researchers isolated and amplified, from Whipple disease tissues, a 16s ribosomal RNA sequence that could only have a bacterial origin [36]. Based on molecular features of the ribosomal RNA molecule, the researchers assigned it to Class Cellulomonadacea, and named the species Tropheryma whipplei, after the man who first described the disease, George Hoyt Whipple.

Particularly noteworthy in the case of Whipple disease is that Koch’s postulates were not satisfied. Koch’s postulates are a set of observations and experimental requirements proposed by Heinrich Hermann Robert Koch in the late 1800s, intended to prove that a particular organism causes a particular infectious disease. For the experimentalist, the most important of the Koch’s postulates require the extraction of the organism from a lesion (i.e., from diseased, infected tissue), the isolation and culture of the organism in the laboratory, and the consistent reproduction of the lesion in an animal injected with the organism. In the case of Whipple disease, the bacterial cause was determined without benefit of isolation or culture. The consistent extraction from Whipple disease tissue of a particular molecule, characteristic of a particular species of bacteria, was deemed sufficient to establish the infectious origin of the disease.

If it were possible to isolate and culture T. whipplei, it is highly unlikely that the disease could be experimentally transmitted to animals or humans; another opportunity to satisfy Koch’s postulates would fail. As a general rule, bacteria in the human body are eaten by macrophages, wherein they are degraded. In the case of Tropheryma whipplei, only a small population of susceptible individuals lacks the ability to destroy T. whipplei organisms. In susceptible individuals, the organisms multiply within macrophages. When organisms are released from dying macrophages, additional macrophages arrive to feed, but this only results in the local accumulation of macrophages bloated by bacteria. Whipple disease is a good example of a disease caused by an organism but dependent on a genetic predisposition, expressed as a defect in innate immunity, specifically a reduction of macrophages expressing CD11b (also known as macrophage-1 antigen) [37] (see Glossary item, Innate immunity).

Aside from our inability to culture and extract the T. whipplei organism, Whipple disease cannot be consistently reproduced in humans because it can only infect and grow in a small portion of the human population. In short, T. Whipplei fails to satisfy Koch’s postulates. As we learn more and more about the complexity of disease causation, formerly useful paradigms such as Koch’s postulates seem inadequate. When we encounter rare diseases of infectious cause, we might expect to find that the pathogenesis of disease (i.e., the biological steps that lead to a clinical phenotype) may require several independent causal events to occur in sequence. In the case of Whipple disease, the infected individual must be exposed to a soil organism, limiting the disease to farmers and gardeners. The organism, residing in the soil, must be ingested, perhaps by the inhalation of dust. The organism must evade degradation by gut macrophages, limiting disease to individuals with a specific type of defect in cell-mediated immunity, and the individual must have disease that is sufficiently active to produce clinical symptoms.

It has been proposed that Koch’s postulates be updated to accommodate modern molecular techniques, and to adjust for the complex ways that organisms interact with humans. The very meaning of biological causation has changed as we learn more and more about disease. We now know that there are many instances wherein the infectious agent cannot account for all of the cellular processes that culminate in disease [38]. The general subject of biological causation will be discussed in Section 9.1.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: infectious disease, microbiology, rare diseases, orphan diseases, orphan drugs, unknown etiology, idiopathic disease, mystery diseases, undetermined origin, unknown origin

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.

Rare Diseases are Sentinels for the Common Diseases

The following text is excerpted from chapter 13 in my newly published book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases

Rare diseases are the sentinels that protect us from common diseases. A few new cases of a rare disease will raise the suspicions of astute public health workers and can warn us that the general population has been exposed to a new or growing environmental hazard. A few new cases of a common diseases will go unnoticed by epidemiologists.

In most instances, a sudden increase in a rare disease has revealed totally unexpected threats to the general population, necessitating enduring improvements in industrial methods and resetting the normal mode of societal behavior. We can trace the origins of chemical carcinogenesis (the study of cancer causes) and of teratogenesis (the study of the causes of congenital malformations) to epidemiologic observations on rare diseases.

There are numerous rare diseases that have served as sentinels for environmental hazards. We listed a few of them in Section 8.4 when we were discussing cancer. Here, we extend the concept to cover all common diseases and we provide the back-stories that clarify the important role of rare diseases in disease prevention and public health.

Here is one example (of many described in the book): Rare mesothelioma caused by asbestos exposure

Asbestos is an insulating material that was used extensively in the mid-twentieth century. Asbestos inhalation is associated with an increased risk of bronchogenic lung cancer, the number one cause of cancer deaths in the U.S. [10]. In most cases of asbestos-related lung cancer, patients have a history of smoking. If asbestos caused bronchogenic lung cancer exclusively, we probably would have no idea of its carcinogenicity, because its effect among the many smoking related lung cancers would be negligible.

In 1960, a link was established between occupational asbestos exposure in miners and rare mesotheliomas of the pleura and peritoneum, the tissues lining the lung cavity and the abdominal cavity, respectively [11]. The news came too late to help individuals who were exposed to asbestos in its heyday, during the booming construction years of World War II. In those days, naval ship-workers, eager to protect vessels from fire, lavished pipes and ceilings with asbestos insulation. In so doing, they exposed themselves to asbestos dust. Their family members, who washed their dusty uniforms, were also exposed. Single exposures to the dust could cause mesotheliomas, and these mesotheliomas tended to occur 20 to 40 years following exposure.

Today, we treat asbestos as a serious occupational and environmental hazard. At enormous cost, we have abated our exposures to asbestos found in attic and pipe insulation, brake liners, and cigarette filters. Once again, occurrences of a rare cancer warned us to take measures to reduce exposure to a hazardous substance. Asbestos carcinogenicity also taught us a new lesson; solid and nonreactive agents could cause cancer.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: endemic, epidemic, epidemiology, genetic disease, health threat, orphan diseases, orphan drugs, public health, rare diseases, sentinel, prevention, rare diseases, genetic diseases

Biological Differences between Rare Cancers and Common Cancers

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. This book builds the case that the best way to advance our understanding of the common diseases is to focus our attention on the rare diseases.

Chapter 8 covers the topic of rare cancers. The rare cancers are biologically different from the common cancers. Chapter 8 explores the biological basis of these differences, and why research into the rare cancers has given us major breakthroughs in the prevention and treatment of all cancers.

Here are some of the biological differences between rare cancers and common cancers:

1. Just a few types of common cancers account for the majority of occurrences of cancer.

2. Most of the different types of cancers are rare cancers. Specifically, there are several thousand rare cancers, and only a few dozen common cancers.

3. Virtually every common cancer is composed of cells derived from the ectodermal or the endodermal layers of the embryo (see Glossary items, Ectoderm, Endoderm). Rare cancers derive from all three germ layers, but the majority of rare cancers derive from the mesoderm.

4. All of the childhood cancers are rare cancers.

5. All the advanced stage cancers that we can currently cure are rare cancers, and most of the curable rare cancers are cancers that occur in children.

6. Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers.

7. Rare cancers are genetically simpler than common cancers (i.e., have fewer mutations). In many cases, we know the underlying mutation that leads to the development of rare cancers. We do not know the underlying mutation(s) that leads to common cancers.

8. Common cancers are genetically heterogeneous and may contain one or more rare types of cancer having the same clinical phenotype as the common cancer.

9. Most of what we know about the pathogenesis of cancer has come from observations on rare cancers.

10. The rare cancers serve as sentinels for environmental agents that can cause various types of cancer; either rare or common. Common cancers cannot serve as sentinels.

11. Treatments developed for the rare cancers will almost certainly apply to the common cancers.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules Berman, Ph.D., M.D.

Rare Diseases are Biologically Different from Common Diseases

As discussed in yesterday's blog, it's not a numerical accident that rare diseases are rare. Biological processes account for the rarity of certain diseases, and for the commonality of common diseases. In my book Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, I explore the fundamental biological differences between rare diseases and common diseases. Here are six observations that distinguish common diseases from rare diseases

1. Rare diseases typically occur in a young population. Common diseases typically occur in adults, increasing in frequency with age.

2. Rare diseases usually occur with a Mendelian pattern of inheritance. The most common diseases may sometimes cluster in families, but they are, without exception, non-Mendelian.

3. Rare diseases often occur as syndromes, involving several organs or physiologic systems, often in surprising ways; most common diseases are non-syndromic. [A syndrome is a constellation of pathologic features associated with a single disease or condition, usually involving multiple organs. For example, inherited deafness is often syndromic. Syndromic deafness is accompanied by other abnormalities, possibly involving facial structure or nerve function. Non-syndromic deafness affects hearing and no other structures or functions.]

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

5. 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, and sometimes on the order of a million-fold.

6. There are many more rare diseases than there are common diseases.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

Rules for the Rare Diseases

It's not a numerical accident that rare diseases are rare. Biological processes account for the rarity of certain diseases, and for the commonality of common diseases. When writing Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, I wanted to establish a set of biological principles that would extend to all the rare diseases and that would help explain the fundamental differences between rare diseases and common diseases.

Biological principles are much like geometric axioms. Once you have your set of principles, you should be able to construct conclusions, rules, and predictions about the behavior of the biological system to which the principles apply. Accordingly, I sprinkle the text of the book with lots of "rules" that follow logically from the first principles of the rare diseases.

The term "rule", in this context, means observations that are generally true. Biology is more messy than geometry. In the book, when the rules are discussed, I might include counter-examples and constraints. The rules are primarily intended to encourage readers to think critically about the subject matter.

There are more than 125 biological "rules" of rare diseases listed through the book. Each rule is followed by a very brief rationale. The rationale for each rule is fully developed in the chapters. I thought it would be fun to construct a button that searches the book, and pulls out a rule randomly from the text, for display in a window. By repeatedly hitting the button, each time it refreshes itself, you can read all the rules contained in the book (if you'd like).

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

The Rationale for Funding Rare Disease Research

This week, my latest book entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Academic Press, an imprint of Elsevier.

The book builds a rationale for increased funding for the rare diseases, and begins with the assertion that it has been much easier to find effective targeted treatments for the rare diseases than for the common diseases. Furthermore, treatments that are effective against rare diseases almost always find a place in the treatment of one or more common diseases. These assertions are not based on wishful thinking, and they are not based on extrapolation from a few past triumphs wherein some treatment overlap has been found in rare and common diseases. These assertions are based on the general finding 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. A smart way to fund medical research is to increase funding for the rare diseases, with the ultimate goal of curing the common diseases.

TABLE OF CONTENTS

Part I. Understanding the Problem.

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

Chapter 2. What are the Common Diseases?

Part II. Rare lessons for Common Diseases.

Chapter 3. Aging.

Chapter 4. Metabolic Diseases.

Chapter 5. Diseases of the Heart and Vessels.

Chapter 6. Infectious Diseases and Immune Disorders.

Chapter 7. Cancer.

Chapter 8. Gastrointestinal and Renal Disorders.

Part III. Fundamental Relationships Between Rare and Common Diseases.

Chapter 9. All Diseases are Complex

Chapter 10. Rare Diseases and Common Diseases: Understanding their fundamental differences.

Chapter 11. Rare Diseases and Common Diseases: Understanding Their Relationships.

Chapter 12. Future Directions.

Glossary.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

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

tags: biology of rare diseases, common diseases, genetic disease, orphan diseases, orphan drugs, rare disease organizations, rare disease research, rare diseases, rare disease funding, rare disease research, funding for rare diseases, importance of rare diseases, funding opportunities, books about rare diseases, books about orphan drugs, orphan drug development