Disease Causality: Unexpected Complexity from Simple Gene Defects

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 points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

A gene may code for a single protein, but complex genetic and epigenetic conditions will effect the individual's response to a specific gene defect. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration. Here is an excerpt from Chapter 9:

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 homologue 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 phosphoribosyl 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 accompanies 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 [18]. 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 (see Glossary item, Transgenic). 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 [19].

I urge you to read more about my 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, common disease, orphan disease, orphan drugs, monogenic disease, complex disease, causality, disease causation, cause of disease, pathogenesis

Medical Causality

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 points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

Here is an excerpt from Chapter 8 [Note: Pathogenesis is the sequence of cellular events that eventually leads to the clinical expression of a disease. Pathogenesis, when restricted to cancer, is known as carcinogenesis.]:

In the field of medicine, we often cannot assign a specific cause to a particular disease without seriously misleading ourselves. For example, what is the cause of rheumatic fever? Rheumatic fever is an autoimmune process that targets the heart. Rheumatic fever occurs in people who have been infected with a Group A strain of Streptococcus pyogenes. The infection, which usually presents as a pharyngitis, elicits an immune response against a bacterial antigen. The antibody species that target the bacterial antigen happen to cross-react with proteins in normal heart and vessels. These cross-reacting antibodies damage the heart and vessels to produce rheumatic fever.

Rheumatic fever is one of the most thoroughly studied and best understood diseases known to man. Knowing all that we know about the pathogenesis, pathology, and clinical features of rheumatic fever, it should be easy to specify the cause of the disease. Alas, this is not the case. For example, we cannot assert that rheumatic fever is caused by Streptococcus pyogenes because not all cases of infection lead to rheumatic fever, and because the clinical features of the disease are not actually caused by the infection. Likewise, we cannot assert that rheumatic fever is an autoimmune disease because it does not result from a defect in the autoimmune response. Basically, rheumatic fever involves a normal immune response to a foreign antigen (i.e., a protein of Streptococcus pyogenes bacteria) that happens to cross-react with the heart proteins. Furthermore, we cannot claim that rheumatic fever is caused by a heart defect; the heart is an innocent bystander in a process that evolved over time in tissues other than the heart (i.e., the pharynx and other tissues in which immunocytes reside). The more we know about the pathogenesis of rheumatic fever, the more difficult it becomes to specify its cause.

What applies generally in medicine will apply equally in the cancer field. Knowing the name of an oncogene that is always expressed in a particular type of cancer may be an important clue to understanding causation and pathogenesis, but it's never the whole story.

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, common disease, orphan disease, orphan drugs, rheumatic fever, rheumatic heart disease, heart disease, immune disease, strep infection, causality, disease causation, cause of disease, pathogenesis