Precision Medicine and the Reinvention of Human Disease (not just about genes)

If everything you know about Precision Medicine comes from the lay press, you may have an unrealistic notion of what's happening in this field. The news seems to stress the one gene -> one disease paradigm that is easy to understand, but largely irrelevant to all the common diseases that occur in humans.

The one gene -> one disease paradigm is this: the clinical expression of each disease is caused by a genetic mutation in a particular gene responsible for that particular disease, or a particular subtype of a disease, in a particular individual. By finding and targeting the gene responsible for an individual's disease, Precision Medicine will cure the patient.

This paradigm is short and sweet, and it is more or less true for a number of rare diseases; but it is wrong for just about every disease that occurs commonly in humans, and it serves to distract our attention from the medical revolution that Precision Medicine will bring.

The purpose of my new book, Precision Medicine and the Reinvention of Human Disease, discussed in previous blogs, is to explain how Precision Medicine is changing our fundamental understanding of the pathogenesis of disease (i.e., the biological steps that lead to the development of diseases), and how this new information is changing the way that we prevent, diagnose, and treat human diseases.

Precision Medicine is not about finding the right gene for the right patient. Precision Medicine is about finding the common events and metabolic pathways that account for the development and the expression of diseases; and using these insights to reduce the morbidity and mortality of disease in the population.

Google Books has a very good "look inside" for my book, and I hope that readers of this blog will take a few moments to see if they might be interested in the subject.

- Jules Berman

key words: precision medicine, jules j berman, Ph.D., M.D., disease biology, pathogenetic, monogenic, rare diseases, complex diseases, common diseases

Precision Medicine and the Reinvention of Human Disease (The Myth)

If you believe the hype, we are entering a new era of medicine in which each individual will receive unique treatment, determined by the sequence of his or her genome. This widely promulgated notion is simply ridiculous. There is no practical way to develop a unique treatment, test the treatment for safety and effectiveness, and titrate the correct dose, all for one person.

The terms "Precision Medicine" and "Personalized Medicine" have given us the false impression that medical science is moving away from off-the-rack remedies and is seeking treatments tailored to the individual. In actuality, science has always been about seeking generalization. When Isaac Newton watched an apple drop, he was not working on a new Law of Falling Apples. He was trying to understand the general laws of gravity and motion that applied to every object in the universe. When Charles Darwin spent 8 years studying barnacles, he was not trying to build a display collection of handsome barnacles for the national museum. He was developing a general theory of evolution that would apply to every living organism on earth. Likewise, when we study a specific pathway that is operative in a small percentage of cases of a rare tumor, accounting for perhaps a dozen patients worldwide, we expect that our findings will have general application to a wide variety of conditions.

Precision Medicine has very little to do with developing unique treatments. Like all medical research, Precision Medicine seeks to find general treatments that will be effective for the largest number of patients. The "Precision" in Precision Medicine refers to our ability to precisely diagnose rare diseases, and subsets of common diseases, that share a particular sensitivity to particular forms of treatment.

- Jules Berman

Rare Disease Day is Here!

It's finally come; the rare day that comes every four years, Rare Disease Day. For the past several weeks, leading up to February 29, I've been blogging about rare diseases. The basic theme of all my blogs is that the rarity of rare diseases is not a numeric accident. The rare diseases form a distinct class of diseases having a distinct set of unifying biological properties that distinguish them from common diseases.

In the past 30 years, most of the great advances of medicine have been in the realm of the rare diseases; not the common diseases. In many cases, progress in the common diseases has come as a secondary gain from discoveries made in rare diseases (e.g., statins to prevent heart disease, new cancer therapies targeted against specific molecules).

You can reverse-page through my recent posts, beginning on this blog page, to get a sense of why the rare diseases deserve our attention. Also, please read my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases, to learn why our best chance to eradicate the common diseases is by funding research in the rare diseases.

- Jules Berman

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, common diseases, complex diseases, medical research, funding for rare disease research,jules j berman

Monogenic Rare Diseases are Surprisingly Complex

"How is it that you keep mutating and can still be the same virus?" - Chuck Palahniuk, in his novel, Invisible Monsters

Monogenic diseases, caused by an aberration in a single gene, account for the majority of rare diseases. Monogenic diseases are the simplest diseases occurring in any organism, and one would think that once we identify the protein coded by the mutant gene, we would fully understand the disease. Nothing could be further from the truth. Knowing the gene, and its protein, may bring us to the root of the disease, but it does not explain how the disease develops; it does not explain the pathogenesis of the disease.

In point of fact, we know very little about the pathogenesis of most of the rare, monogenic diseases. When we try to study the pathogenesis of rare diseases, we quickly learn that they are much more complex than we had imagined. The complexity derives from the general biological properties of genes and of the cellular processes that influence the expression of genes. Let us examine a partial list of factors that add to the complexity of monogenic diseases.

1. 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

There are hundreds of examples of single genes that can produce more than one disease. Appendix I from my book, Rare Diseases and Orphan Drugs, contains a list of approximately 170 genes, with each gene known to be the underlying cause of more than one listed genetic diseases.

The disease caused by a gene may change depending on whether the gene is expressed as a germline mutation or a somatic mutation. In the case of the MYCN gene, a germline mutation resulting in MYCN gene haploinsufficiency (i.e., for which one gene is non-functional while the gene on its matching chromosome expresses a normal gene product) may produce Feingold syndrome, a developmental disorder characterized by microcephaly, limb malformations, esophageal and duodenal atresias, and other developmental alterations. The same gene, occurring in somatic cells (i.e., as new mutations in tissue cells of adult organisms), as an amplified gene, is associated with neuroblastoma formation.

In some cases, the diseases produced by a specific genetic mutation will change depending on the mutation's parental lineage. Prader-Willi syndrome is a genetic disease characterized by growth disorders (e.g., low muscle tone, short stature, extreme obesity, and cognitive disabilities). Angelman syndrome is a genetic disease characterized by neurologic disturbances (e.g., seizures, sleep disturbances, hand-flapping), and a typifying happy demeanor. Both diseases can occur in either gender and both diseases are caused by the same microdeletion at 15q11-13. When the microdeletion occurs on the paternally-derived chromosome, the disease that results is Prader-Willi syndrome. When the microdeletion occurs on the maternally-derived chromosome, the disease that results is Angelman syndrome.

In some cases, variation in the sites of mutations in a gene do not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott-Aldrich syndrome, 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 (1).

In some cases, the gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, 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 (2). Beckwith-Wiedemann syndrome is characterized by tissue overgrowth and tumor formation (3). Russell-Silver syndrome is characterized by dwarfism.

2. A single gene may encode a regulatory protein that effects many other proteins, to produce a disease that affects many different tissues, through unrelated mechanisms. It may be difficult or impossible to determine all the different proteins and pathways that are altered by a defective regulatory gene.

In general, diseases due to genes encoding transcription factors are characterized by multiple anomalies of development and growth. Transcription factors are proteins that bind to specific DNA sequences to control the transcription of DNA to RNA. A mutation in a single transcription factor can produce a phenotypically complex syndrome. For example a mutation in the gene encoding transcription factor TBX5 causes Holt-Oram syndrome, consisting of hand malformations, heart defects and other malformations.

3. A protein with a single function may exert a pleiotypic response in different types of cells and tissues, causing may different phenotypic changes in tissues, to produce a seemingly complex disease phenotype.

Consider the example of the rare disease, ligneous conjunctivitis. Ligneous conjunctivitis is caused by a deficiency of a single protein, plasminogen. Plasmin, the activated form of plasminogen, breaks down fibrin, a protein produced during coagulation and clot formation. In the absence of plasminogen, fibrin accumulates in various sites, and the accumulating fibrin dries out as a hard material. On the surface of the eyes, dried fibrin elicits inflammation, leading to a thick, hardened focus of conjunctivitis (i.e., ligneous conjunctivitis). Accumulating fibrin in the middle ear and the tracheo-bronchial mucosa (of the lungs), leads to inflammation at these sites. In the brain, an occlusive hydrocephalus may occur, due to fibrin deposits blocking the normal flow and clearance of cerebrospinal fluid in the brain ventricles. In retrospect, the pathogenesis of ligneous conjunctivitis is simple to understand. All of the pleiotrophic effects are the result of a deficiency of a single protein, with a single function, that happens to be expressed in several different organs to produce a variety of clinical conditions that are closely related to one another; but not obviously so. Ligneous conjunctivitis is an example of the simplest form of pleiotropism, wherein seemingly unrelated phenotypes result from an alteration in a single expressed protein, and a single functional pathway.

Another example of pleiotypia resulting from a gene with a single function is found in the WHIM syndrome. WHIM is an acronym for Warts, Hypogammaglobulinemia, Infections and Myelokathexis (congenital leukopenia and neutropenia). We now know that WHIM is a combined immunodeficiency disease caused by an alteration in the chemokine receptor gene CXCR4 (4). Warts result from a lowered immune repression of papillomaviruses. Likewise, the other phenotypic components of the disease arise from the aberrant chemokine. Though the altered CXCR4 gene produces a syndrome with a complex phenotype, it does so through the action of one protein with one function.

4. A protein with a single function may exert a single type of response, but that response may depend on the genetic and epigenetic conditions under which the protein is expressed. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration.

If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical, in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse. If the mouse homolog served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same, in man and mouse.

Lesch-Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphporibosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompany the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal (5). How can this be? A single gene cannot cause a disease, all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.

Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY. Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene (6).

Though there is often striking phenotypic homogeneity among humans with the same genetic defect, there are many exceptions. Modifier genes can influence the time of onset of disease, the severity of disease, and the clinical phenotype of genetic diseases (7).

5. A single protein encoded by a single gene may have many different biological effects and functions, and these functions may differ based on the cell type in which the protein is expressed, the stage of development in which the protein is expressed, and the cellular milieu (e.g., concentrations of substrate or protein inhibitors) for a given cell type, at a particular moment in time. Hence, a specific aberration in a single gene may produce different diseases, depending on factors that are difficult to anticipate or analyze.

Sometimes, one gene may code for a protein that has multiple different roles, thus producing diseases of widely disparate clinical phenotypes. For example, nuclear lamina (lamin a/c) has several biological roles: controlling nuclear shape; influencing transcription; and organizing heterochromatin. Mutations in the LMNA gene cause more than 10 different clinical syndromes, including neuromuscular and cardiac disorders, premature aging disorders, and lipodystrophy. Likewise, the polyfunctional TP53 gene has been linked to 11 clinically distinguishable cancer related disorders (8).

Rule - A single pleiotropic gene is likely to be associated with several phenotypically unrelated diseases.
Brief Rationale - Genes with pleiotropic pathological effects, and genes that alter a pathway that operates in many different types of cells, are likely to play a role in the pathogenesis of more than one disease, simply because they perturb many different cellular processes.

A bull in a china shop will do more damage than a mouse in a china shop. For example, The APOE gene encodes apolipoprotein E, which is involved in the synthesis of lipoproteins. One common allele of the APOE locus, e4, increases the risk of two common diseases with no obvious biological relationship: Alzheimer disease and heart disease (9), (10). A rare locus of APOE is a associated with longevity (11).

6. The pathogenesis of a monogenic disease may be complex, requiring many events to occur in a particular sequence, over a period of time, culminating in a disease phenotype. Deviations from the usual steps in pathogenesis may delay or eliminate the occurrence of disease.

Many of the rare monogenic diseases express a characteristic clinical phenotype at birth (e.g., birth defects), or in early childhood. A minority of rare, monogenic diseases are not expressed until adulthood. What can we infer from this observation?

Rule - Monogenic rare diseases that express in late adolescence, or in adulthood, are likely to require additional events (i.e., somatic genetic mutations, toxic exposures, or the accumulation of molecular species or cellular alterations caused by the original genetic defect) that occur over time.
Brief Rationale - If this were not the case, every inherited genetic defect would be expected to express itself clinically at birth or in early childhood.

The many inherited cancer syndromes produce tumors in a younger age group than the same tumors that occur sporadically. Still, these inherited tumors tend to occur in early or mid-adulthood, not at or near birth. Cancer is a multi-step process. An inherited mutation that accounts for one step in the process may shorten the time for development of the cancer, but it cannot eliminate the remaining steps.

Huntington disease is a rare monogenic inherited disease that usually begins in adults between 35 and 45 years of age. It is caused by a CAG triplet repeat inside the Huntington gene. The mutant gene slowly poisons brain cells, particularly neurons in the caudate nucleus, putamen, and substantia nigra. The toxic effects of the mutant protein are slow to cause injury, hence the late onset of disease.

Cardiofaciocutaneous syndrome is a rare monogenic inherited disorder characterized by a set of distinctive congenital abnormalities involving the face, heart, and other organs. It is caused by mutations in any of several different genes, including BRAF. In a zebrafish model of cardiofaciocutaneous syndrome, fish embryos express the BRAF disease allele. Treatment of the affected embryos with inhibitors of the pathway affected by the BRAF mutation will restore normal development in these fish (12). The inhibitor needed to be administered in a window of time when the BRAF mutation exerted its teratogenic effect. In this case, the pathogenesis of disease could be interrupted by an additional event occurring at a crucial moment of time.

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Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, monogenic diseases, complex diseases, common diseases, jules j berman

References:

[1] Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood 104:4010-4019, 2004.

[2] Soejima H, Higashimoto K. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. J Hum Genet 58:402-409, 2013.

[3] Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 18:8-14, 2010.

[4] Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70-74, 2003.

[5] Engle SJ, Womer DE, Davies PM, Boivin G, Sahota A, Simmonds HA, et al. HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome. Hum Mol Genet 5:1607-1610, 1996.

[6] Raeder H, Vesterhus M, El Ouaamari A, Paulo JA, McAllister FE, Liew CW, et al. Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PLoS One 8:e60229, 2013.

[7] Nebert DW, Zhang G, Vesell ES. From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metab Rev 40:187-224, 2008.

[8] Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 408:307-310, 2000.

[9] Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant . . . or not? Human Molecular Genetics 11:2417-2423, 2002.

[10] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 261:921-923, 1993.

[11] Beekman M, Blanch H, Perola M, Hervonen A, Bezrukov V, Sikora E, et al. Genome-wide linkage analysis for human longevity: genetics of healthy aging study. Aging Cell 12:184-193, 2013.

[12] Anastasaki C, Estep AL, Marais R, Rauen KA, Patton EE. Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Hum Molec Genet 18:2543-2554, 2009.

Rules for Rare Diseases

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

For today, please consider these three biological "Rules" that I use when I'm trying to convince my colleagues of the importance of rare disease research.

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 the 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 (1).

Rule - Every common disease is a collection of different diseases that happen to have the same clinical 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 dozens, many hundreds of 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 disease that account for a small subset of cases.

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 (2).

[1] 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.

[2] Stossel TP. The discovery of statins. Cell 134:903-905, 2008.

- Jules Berman (copyrighted material)

key words: rare diseases, biological rules, disease funding, common diseases, complex diseases, precision medicine, jules j berman

Rare Diseases and Orphan Drugs: Recent Blogs

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.

Over the past several weeks, I've been posting to several different blogs on the subject of rare diseases.

Here is the list of my rare disease posts, with links:

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

Rare Diseases Account for Subsets of Common Diseases

Phenocopy Mimics of Rare Diseases: Lessons for the Common Diseases

Phenocopy Diseases: Their Relationship to Rare Diseases and Common Diseases

What Rare Diseases Teach Us About the Cellular Basis of Aging

What is the Fundamental Biological Process that Causes Aging?

Wrinkling and Sagging are Chronic Toxic Processes Not Directly Caused by Aging

Disease Complexity: Rare Diseases and Common Diseases

Case Reports of Rare Diseases Have General Value

When Rare Diseases and Common Diseases Converge to Same Clinical Picture

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

Rare Disease Legislation in the U.S.

Definition of Rare Disease

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

Rare Diseases Account for Subsets of Common Diseases

Improving Clinical Trials by Focusing on Rare Diseases

Rare Diseases of Unknown Origin

Rare Diseases are Sentinels for the Common Diseases

Biological Differences between Rare Cancers and Common Cancers

Rare Diseases are Biologically Different from Common Diseases

Rare Cancers are Biologically Different from Common Cancers

Rare Cancers

Clinical Trials and Rare Diseases

Rules for the Rare Diseases

The Rationale for Funding Rare Disease Research

New Book Explains the Importance of Rare Disease Research

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you think that you and your colleagues may benefit from reading this 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 diseases, orphan drugs, funding opportunities, rare cancers, common diseases, complex diseases, clinical trials, rare disease organizations, disease advocates

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

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 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.

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.

New Book Explains the Importance of 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 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.

The following text is excerpted from the book's Preface.

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 sub-disciplines 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 of 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.

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.