PRECISION MEDICINE

Precision Medicine is an strange term. It invokes an image of carefully crafted exactness rather than the reality: medicine is an inexact science - bounded in humility. So those of us looking around the corner for the Golden Age of Medicine need to calm their caffeinated jitters.

Articles abound in scientific literature and increasingly in the lay publications. Authors are doing cartwheels and stepping over each other in the trail of this magically transforming triumphant approach to treatment of human disease. Some claim that human illness will soon be eradicated. The hubris astounds.

Let us look at some of the pitfalls for now, not to be distracted by an anecdote of how this or that person was cured from an incurable malady. Plenty of that anecdotal material can be found in the New York Times and other papers.

The human body has about 25,000 functioning genes, made from the linkage of four nucleic acids Adenine, Thymine, Guanine and Cytosine or A,T,G,C. From these humble beginning a population of 7.1 billion diverse human beings currently occupies the planet. (Malhus must be turning over by now). Each individual, shares the same genetic structure but there are subtle changes in each human being’s DNA that give us our looks, morphology (body structure), intellect, nuanced behavior and other things that are nurtured by the environment. And thus, although monozygotic twins share a 100% of their DNA they too have subtle differences in their gene structures over time based on difference of life experience – the Lamarckian twist!

So in a population of say 1000 people who are not related to each other what is the probability that they will share identical genomic signatures for a given disease. The answer comes from various studies including the one carried out by Mary Claire King looking at the prevalence of BRCA (BReast CAncer gene) mutations. These mutations are at best in 14% of the population and seem to be more prevalent in for example the Ashkenazi Jewish population subset.

Another study in Lung Cancer determined that EGFR (Epidermal Growth Factor Receptor) mutations are found in 15% of the population, or the ALK (Anaplastic Lymphoma Kinase) mutation in the same patients with lung cancer occurred in 5% of the cohort studied.

So then the saying goes, well, if we find the genetic structure we can treat effectively. Effectively, yes. But cure a disease? Not so quick my dear Watson. One might think that if we can study these genomic discrepancies, and then devise therapy selectively for the cohort with the anomalous findings. Ah but here is the $64,000 conundrum: What epigenetic signatures modify the behavior of those genetic signatures still remains unknown. So one might have the SNP (Single Nucleotide Polymorphisms) or CNV (copy number variations) or a substitution of A for C in the DNA but how that is expressed might be in the hands of a lesser known but equally strong power called the micro RNA that might be perched around the gene to mess with its behavior.  Or even the semi fluid control of the Transposons, the genes that jump for the sake of strengthening the survival of the DNA and can inadvertently sit and silence a tumor suppressor gene or over-express a proto-oncogene to accelerate cancer growth. So responses even with known gene abnormalities differ as a consequence of the epigenetic deliverance. Not to forget that the cancer cell within its interior has multiple pathways, which govern the behavior of the nuclear proliferation and hence doubling of the cell. So silencing a gene that provokes the proliferation pathway may be silenced temporarily by an antidote (monoclonal antibody or mAb) that attacks the functional protein product of the gene only to be thwarted by an overactive collateral pathway that gets recruited to continue the wayward cell growth.

Recently reported scientists have discovered a gene called GNAS c.393C;T that seems to cause Ventricular arrhythmogenesis (causing arrhythmia or irregular heart rhythm) and is now thought to be associated with sudden cardiac death. With a HR of 1.2 and a P-value of 0.039, clearly more study needs to be done before we start inserting pacer/defibrillators in people with this genetic anomaly.

A study in the NEJM recently showed that targeting a select molecule (BRAF) in different cancers where its expression is evident yields mixed results at best. and goes to the original Shakespearean premise that "there are more things in this heaven and earth (Horatio) than are dreamt of in (y)our philosophy."

So precision is imprecise at best. Before we start building models of costs, quality and exactness, a tincture of humility might also be in order. Such bravado needs some careful reckoning before we hail the next coming of sliced bread. You know, it would be nice to just call it Medicine for now!