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

Phenocopy Mimics of Rare Diseases: Lessons for the 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.

The topic of phenocopy diseases was introduced in yesterday's blog post. Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired von Willebrand disease [the phenocopy disease] and inherited von Willebrand disease [the genetic disease]

Von Willebrand factor is a complex protein, the largest protein found in plasma, and is required for platelet adhesion. Reduction in von Willebrand factor results in a clotting disorder. Von Willebrand disease can result from inherited deficiency or it can be acquired through several mechanisms. In an autoimmune variant of the disease, antibodies reacting with the factor produce a protein complex that is rapidly cleared, effectively producing a deficiency. As a large, complex molecule, von Willebrand factor is particularly vulnerable to mechanical disruption. Artificial heart valves have been observed to produce von Willebrand disease. In cases of thrombocythemia (i.e., increased numbers of platelets in blood), excess platelets can absorb the von Willebrand factor to produce a functional deficiency.

From observations of many phenocopy diseases, we can make the following generalization, discussed in Chapter 9 of my book:

9.5.1 Rule—Phenocopy diseases are typically mimics of rare diseases, not common diseases. Brief Rationale—The prototypical phenocopy disease involves a single agent having a specific effect on a single pathway in a limited number of cell types.

In theory, any pathway can be altered by a drug to produce a phenotype that mimics a monogenic disease. A simple interruption of normal cellular function of a gene or a pathway is consistent with what we see in rare diseases and in phenocopy diseases, and lacks the cumulative acquisition of multiple genetic or cellular aberrations that typically characterize the common diseases. Phenocopy diseases provide important clues to the pathogenesis of rare and common diseases for the following reasons:

1. There is usually one pathway involved, often found in a limited number of cell types, and the phenocopy disease teaches us how this pathway operates and how it can be disrupted.

2. The pathway disrupted in the phenocopy disease is almost always the same pathway that is disrupted in the rare genetic disease. Hence, the phenocopy tells us how the rare disease expresses itself, and this is something that we can seldom infer from our knowledge of the gene mutation associated with the rare disease.

3. When the genetic cause of the rare disease is unknown, the careful study of its phenocopy will always yield a set of candidate genes that may operate in the rare disease.

4. Pharmacologic treatments for the phenocopy disease may apply to pathways operative in the genetic form of the disease or in the common diseases.

5. The pathway involved in a phenocopy disease can contribute to the pathogenesis of a common disease. Hence, understanding the phenocopy diseases brings us a little closer to understanding common diseases [60]. This topic will be discussed further in Chapter 10.

6. Recognizing the cause of a phenocopy disease may curtail potential environmental catastrophes.

The phenocopy diseases help us to focus on the cellular pathways leading to disease. If you exclusively study the genetics of disease, you will likely miss the cellular pathways that link rare diseases with common diseases.

The phenocopy diseases remind us that you can have a disease without a causal gene, but you cannot have a disease without a causal pathway.

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, phenocopy disease, mimics of disease, principles of pathology, complex disease, disease biology, pathogenesis

Phenocopy Diseases: Their Relationship to 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.

Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired conduction defect [the phenocopy disease] and inherited conduction defect [the rare, genetic disease that is copied by the phenocopy disease]

Disorders of ion flux across membranes are known as channelopathies. The inherited cardiac conduction channelopathies were discussed in Section 5.3.

Because the anti-arrhythmogenic and anti-epileptic drugs typically target ion channels, they are the drugs most likely to produce, as an adverse side effect, disorders of cardiac conduction. For example, rufinamide, an oral antiepileptic drug, has been reported to cause QT-interval shortening [44]. Quinidine, disopyramide, and procainamide have been reported to produce QT prolongation [45].

Several channelopathies can be acquired as autoimmune diseases, in which antibodies react with ion channels, or related cellular components upon which the ion channels depend (e.g., myasthenia gravis, Lambert–Eaton myasthenic syndrome, cerebellar ataxia associated with VGCC antibodies, acquired neuromyotonia, Morvan fibrillary chorea, limbic encephalitis) [46].

Progressive familial heart block type IA is a genetic disorder of the cardiac conduction system. Clinically similar conditions can be acquired when the tissues of the conduction systems are damaged, as in: myocardial infarct, conduction system ischemia (i.e., lack of blood flow to components of the conduction system, particularly the His–Purkinje conduction tissue), age-related degeneration of conduction system, and complications of procedures (i.e., insertion of wires or lines into the heart chambers) [47].

The importance of the phenocopy diseases to our general understanding of disease processes, and to the development of successful treatments for rare diseases and common diseases, will be discussed in the next few blogs.

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, phenocopy disease, complex disease, heart block, arrhythmia, disease biology, pathogenesis