Final copy. GENES, DREAMS, AND REALITIES IN HYPERTENSION.
Posted by bmhegde on 1
Just as people believe that there is a pill for every ill, we have been hoping that with the unravelling of the genome most of our knotty problems in hypertensive diseases would vanish into the thin air. The truth is otherwise. I do not think that the genome would make life any easier for either the doctor or the patient in this field, at least in the foreseeable future.
The first surprise has been that instead of the projected 100,000-150,000 genes, the final picture gives us just about double the number of genes compared to a round worm-around 30,000-40,000 genes. Obviously, there are not enough genes to go round giving a gene for every human ill! On the contrary, prior knowledge of the genome would certainly make life miserable for the unfortunate person who might inherit some of the killer genes. While the gene's absence reasonably rules out the future occurrence of that disease, its presence, in no way, ensures that the disease would manifest for certain. The penetrance of the gene depends, to a great extent, on the environment. However, the child who knows its genome has to live with the Damocles' sword on its head all its life! Our dreams in this filed have never been realised. The reality is otherwise. My predictions in this field have come true!1
Time evolution in any dynamic system, like the human body, does not depend on partial knowledge of the organism, like the genome. Instead, it depends on the total initial knowledge of the organism. In case of man the total knowledge should include the phenotype (body characters like height, weight, BMI, BP, Cholesterol etc), the genome, and, most importantly, his consciousness. Mind, body and the genotype together make a man and all predictions of the future would be wrong if not based on all these three. Sage Kapila, thousands of years ago, had predicted the role of chromosomes and genes (beejaaha, beejabaghaha) in disease predictions along with the body and the mind! We have been all along predicting the unpredictable in medicine.2
In the early 50s, there was a real war of words between two giants in the field of hypertension, Sir George Pickering and Lord Platt, regarding the genetic basis of hypertension. While Sir George was emphatic that hypertension could only be a polygenetic trait, Lord Platt argued that a single gene must be the cause of hypertension. This led to both writing extensively in The Lancet that at one stage, a serious reader had to ask the editor for a moratorium on their views! Time has proved both to be partially right! While there are single gene defect rare congenital hypertensive disease states like the Liddle's syndrome, the common variety of hypertension, the primary hypertension, is definitely polygenetic in nature.
Heritability:
It is impossible to assess the isolated role of the genes in one's blood pressure reading. If one has a BP level of 190/120 mm. Hg, it is impossible to say as to how much of that pressure is due to his genes and how much is otherwise. Heritability of hypertension, therefore, is impossible to assess by any means. As mentioned earlier any disease manifestation is the interplay of three factors-the mind, the gene and the environment of the patient. The concept of heritability, therefore, is not valid in this situation.
Advances in Genetics:
Little known work of the Nobel laureate, Baraba McClintock, shows that genetic code of an organism"is not a static blueprint that can be read off like a book, but flexible, dynamic code responding to the surrounding environment". Her notion of the dynamic genome, expressed as the "jumping genes" has revolutionised genetics!3 Interestingly, Barbara has said that she came to this conclusion by "listening" to her corn plants and trying to see the world from their perspective.
We need more such thinking scientists in the field human genetics to lessen the sorrow of the prior knowledge of the genome in the future generations. "Happiness is living dangerously" is a thought-provoking adage in an English Primary School. Man is happy in this world only because man does not know his future. Now that the genome is threatening to become a reality, many would be miserable indeed!
Another related work that has opened a new vista for medical science is the outstanding work of Lynn Marqualis on cell symbiosis. This highlights the role of co-operation rather than competition among organisms! This goes against the grain of existing medical thought about the fight against germs which; we are slowly, but definitely, losing with the emergence of multi-drug resistant strains of almost all-common germs!
Nuts and Bolts of Genetics in Hypertension:
Essential hypertension is not a single entity. It is a clinical mosaic with multiple syndromes. Our search for an answer to the problem of hypertension through genetic wisdom has been like chasing the ghost. From the "thrifty" genes that we have inherited because of the thousands of years of scarce food, we have, in the last one hundred odd years, put ourselves in the food plenty atmosphere. This gene-food mismatch has been responsible for many a human illness. Many hypertension related genes have been studied to date; the prominent among them are the nitric oxide synthase gene, endothelial sodium channel regulator genes, insulin sensitivity related ones, and many others. However, to date none of the genes could be definitely labelled to be solely responsible. Genotype-phenotype interaction could be more important than the role of the gene alone. 4 It is almost impossible to assign a role to individual genes in a mosaic like hypertension. Even our attempts to assess gene therapy in modulating and controlling blood pressure have come to naught so far. Although it would be an ideal situation if gene therapy could control the elevated blood pressure on a long term basis, avoiding the risk of drug side effects on life long therapy as also to avoid the problems of non-compliance. But this euthopia still remains a mirage in 2001. Man lives on hope and we hope that one day we will be able to crack the knot. The pace of gene research is mind boggling to say the least. 5, 6
Conclusions:
We are back to the square one. As stated earlier, our modern medical research is linear and reductionist. The whole need not be the sum total of the bits. The whole remains a whole and works like a whole. Genotype, phenotype, and the human mind must be assessed in toto to solve any problem of mankind. No short cuts would help. In the distant horizon is the new science of chaos and fractals that would integrate all these in the non-linear holistic future research. Already some progress has been made in this direction.7, 8.
No single effort would yield results in such a complicated syndrome like hypertension where the only measurable factor is the level of blood pressure. Even the very basis of blood pressure as a product of cardiac output and peripheral resistance is based on wrong science and is not the whole truth. One can only gauze the depth of our ignorance in this field. Only when there is so much of confusion do new wisdom and new directions emerge.
BIBLIOGRAPHY.
1. Hegde BM. Genes, dreams, and realities. Postgraduate Medicine (book) ed. Munjal YP. API Books 1999.
2. Firth WJ. Chaos-Predicting the unpredictable. BMJ 1991; 303: 1565-1568.
3. Wertheim M. Feature. S.G.I.Quarterly 2001; 26: 2-8.
4. Tiago AD, Nkeh B, Candy GP et. al. Association study of eight candidate genes with renin status in mild-moderate hypertension in Africans. Cardiovasc.J.S. Afri. 2001; 12: 75-80
5. Warnock DG. Genetic forms of human hypertension. Curr. Opin. Nephrol. Hypertens 2001; 10: 493-499.
6. Smithies O. Quantitative genetic variations in essential hypertension. Harvey Lectures 1999-2000; 95: 1-20
7. Hegde BM. Chaos- a new concept in science. Jr.Assoc. Physi. India. 1996; 44: 167-168.
8. Hegde BM. Heart Rate Variability (HRV) - a non-linear measure. Autonomic Nerv. System. 2001 October Issue (in Press)