Genes

Genes2017-09-07T20:21:51+00:00

Genes 

Historians of the future are likely to regard the 20th century as the dawn of the age of disease management. It’s hard to think of a decade that didn’t see an important new drug or family of agents “go live” (see table)

Genes Table image from New Medical Terms

Lifesaving drugs of the 20th century

The above medications have saved hundreds of millions of lives and increased the average human life by 10 or more years. However, the operative word as relates to many of these life-saving wonder drugs is management, not treatment. 

Differentiating between the management and treatment of disease is not an exercise in idle semantics. When we manage a disease, we control its symptoms and alleviate the patient’s suffering. Heart failure is a classic example of a condition that is exquisitely sensitive to the yin-yang of disease management. Excessive intravascular fluids exacerbates the symptoms of failure, mandating diuresis; excessive diuresis reduces cardiac output, causing peripheral symptoms; it’s a game of pharmacologic titration that balances competing morbidities. Whilst the 20th century’s paradigm of management is certainly better than what we had to offer patients in the 19th century, it falls short of treatment, in which the structural and functional causes of the disease are corrected (treated). 

As the 20th century was winding down, a highly ambitious “Big Science” project was launched, that of sequencing the human genome. In 2001, the battalion of publicly- and privately-funded biomedical researchers involved in this holy grail of human genetics delivered the draft genome sequence; in 2004, they delivered the complete sequence. Interpreting and analyzing the data from the 3.3 billion base pairs of DNA is still in its early stages. Thus far we know:

• There are ± 22,300 protein-coding genes

• There is far more segmental duplication than initially thought

• Less than 10% of protein families are vertebrate-specific

Since 2004, a tsunami of diseases have been linked to defective genes, changing the landscape of disease nomenclature and how diseases will be treated (not merely managed) in the not-too-distant future. 

molar tooth sign image from New Medical Terms

molar tooth sign

As a concrete example, in 1969, M Joubert et al described a condition structurally characterized by agenesis of the cerebellar vermis and functionally characterized by episodic hyperpnea, abnormal eye movements, ataxia and mental retardation, and a highly characteristic finding by neuroradiology, the so-called molar tooth sign (see image). As typically happens when a new cluster of specific findings are described, we call it X syndrome, after the author or authors who first described the complex, here, Joubert syndrome.*

*It ain’t rocket science, people. 

The patients described by Joubert were 4 French Canadian sibs, born of distantly related parents, fulfilling the criteria of autosomal recessive inheritance. For the next half century, other cases and cohorts were found with the above indicated clinical and neuroradiologic findings and dutifully labelled Joubert syndrome. Then along come the data from the Human Genome Project, screwing up everything once known as Joubert syndrome. The first cohort with Joubert syndrome to be studied genetically (Bielas et al, 2009) had a defect in INPP5E, the gene that encodes inositol polyphosphate-5-phosphatase E, an enzyme which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimuli. 

Logic dictates that all other patients with Joubert syndrome would have the same defective gene. 

We should be so lucky…

In 2010, Edvardson et al reported 13 individuals from 8 inbred Ashkenazi Jewish families, who had defects of TMEM216, a gene which encodes a transmembrane domain-containing protein required for tissue-specific ciliogenesis. Because these patients differed genetically from the first group (which have a defect in INPP5E), the former have what is now known as Joubert syndrome 1, the latter (which have a defect in TMEM216) as Joubert syndrome 2. In 2011, Najmabadi et al linked another defective gene, AHI1, which encodes Abelson helper integration site 1, a protein required for normal cerebellar and cortical development to Joubert syndrome, which has been labelled Joubert syndrome 3. 

Are you seeing the pattern?

At last count, there were 29 different Joubert syndromes, each caused by a defect of a different gene. Tweaking the gene linked to a particular form of Joubert syndrome, and only that gene, will treat the disease. Correction of gene defects is moving forward along various fronts, from maneuvers as simple as dietary supplementation, reported in mid-2017 (N Engl J Med 2017; 377:544-552 August 10, 2017 DOI: 10.1056/NEJMoa1616361) to manipulation of the genes themselves, on the rapidly approaching horizon with CRISPR and other tools being used to edit genes. The 21st century will be known as the dawn of the age of treatment…

References

https://en.wikipedia.org/wiki/Arsphenamine

https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines#Lipid-lowering_agents

https://en.wikipedia.org/wiki/Human_Genome_Project