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Biotechnology and Society---Part V
Genetic Diseases – Sickle Cell Anaemia
Many things grow in the garden that were never sowed there.
----Proverb
We discussed the linkage between the DNA blueprint and the incidence of genetic diseases in the previous articles. There are more than 60 well characterised genetic disorders (as to their causes, symptoms and possible treatments) in addition to many others which are only recognised as genetic diseases. Some of the common genetic disorders are Canavan disease, Cystic fibrosis, Down syndrome, Gaucher disease, Huntington disease, Marfan syndrome, Tay-Sachs disease, Urea cycle disorder and Wilson’s disease. Some of these diseases result from a faulty gene inherited from one parent, some from both parents, and some others through spontaneous mutation in the foetus under development, or even in adult life.
There are also instances where the original blueprint gets modified by the environment (both micro- and macro) and the ripple effect it generates leads to some undesirable consequences. Let us examine a disease which conforms to this pattern here.
Sickle Cell Anaemia (SCA): This is an inherited blood disorder characterised by chronic anemia and recurrent episodes of pain. It is an autosomal (not X-related) recessive genetic disorder in Chromosome 11 caused by a defect in the haemoglobin (Hb) gene. The presence of two defective genes in a person (one from each parent) causes the disease. The risk is the same whether the person is male or female. If there is a normal gene
(A) and a defective gene (S), the person is not affected but he/she is called a “carrier”. If two carriers,
AS (one male and one female) marry, the offspring have a 25 per cent chance of inheriting two defective genes
(SS) and thus the disease.
SCA affects millions throughout the world. It is common among people whose ancestors come from sub-Saharan Africa, South America, Cuba, Central America, Saudi Arabia, India, Greece, Italy and Turkey.
 The underlying problem involves haemoglobin, the primary protein in red blood cells (RBC). Of the total 574 amino acids (basic building blocks of proteins) in Hb, just two of them have been changed due to a mutation in the codons (triplet base unit in the gene). When this happens, the Hb after delivering oxygen to the tissues, gets distorted in structure and cluster with other Hb molecules forming long rod-like structures progressing to a rigid gel. These structures cause the RBCs to become stiff and assume a sickle shape. Normal red cells are smooth and doughnut-shaped (see figure) and are able to negotiate a smooth passage through the capillaries in the blood vessels. The sickled red cells cannot squeeze through the narrow capillaries and thus get stuck and cause blockages that deprive the organs and tissues of the needed oxygen carried by the hemoglobin. This results in pain and damage to vital tissues and organs. In addition, the sickled red cells die after only 10 to 20 days compared with the normal life span of 120 days for normal red cells. Since they cannot be replaced soon enough, the blood is chronically short of RBCs, a condition called anaemia.
 The clinical course of SCA does not follow a simple pattern, some patients have mild symptoms while others have severe ones. Pain and swelling in hands and feet, fatigue and shortness of breath, retinal damage, yellowing of the skin and eyes, delayed growth and puberty in children are some of the common symptoms. In addition, the patients are also subject to recurrent infections, chest pain and even stroke.
Early diagnosis of SCA is critical so the children can get proper treatment. A diagnostic test is carried out to identify and confirm the presence of the defective haemoglobin (HbS) molecule. If confirmed, the patient is slated for appropriate care.
Currently there is no cure for SCA. Basic treatment of a painful crises relies heavily on painkilling drugs and oral and intravenous fluids to reduce pain. Blood transfusions help correct anaemia by increasing the number of normal RBCs. Oral administration of penicillin can prevent pneumococcal infection in children. These treatments are just temporary measures to ward off the crises.
The real breakthrough in treatment requires more research. In 1995 the US National Institute of Health (NIH) conducted some clinical trials using an anti-cancer drug called
hydroxyurea and found that daily doses of this drug reduced the frequency of painful crises and acute chest syndrome in adults. It is now an approved drug for adult patients. Another experimental chemical called
butyrate (normally used as a food additive) is also being investigated. These two chemicals are thought to increase the level of foetal Hb, an analog of Hb produced in the foetus when it is in the mother’s womb but whose production is turned off once the baby is delivered. The foetal haemoglobin is known to prevent the gelling of HbS when mixed with it and prevent the sickling of the red cells. Hydroxyurea is thought to switch the foetal haemoglobin gene “on”. If the foetal haemoglobin gene can be inserted into the patients, that would be a permanent solution. More research in this area as to how genes are turned on and off should lead to new therapeutic approaches for total management of the disease. Until then, screening of potential marriage partners as carriers of the trait and proper genetic counselling either to avoid such marriages or, if they do occur, to avoid begetting children are probably the best preventive measures.
Etiology of SCA: We indicated earlier that most genetic disorders are caused by random mutations in the genes occurring during DNA replication. However, the mutation in the gene for haemoglobin was not just an error in replication but an evolutionary adaptation necessitated by the onslaught of a malarial epidemic. Is there a method in the madness? Let us emphasise here, lest it should be misunderstood, Darwin’s theory of evolution holds that organisms do not and cannot evolve just because they “need” or “want” to change. The random mutations, which prove beneficial against natural disasters or epidemic, tend to get perpetuated thus conferring a survival advantage.
In 1946, an observant physician in Zimbabwe (formerly Rhodesia) saw a correlation between the HbS and resistance to malaria. According to his observations, children who carried a single copy of the defective gene seemed more resistant to malaria than children who didn’t carry it.
 <<--- Mosquito involved in transmission of malarial parasite.
Epidemiological investigations revealed that wherever malaria was rampant, the defective gene was present in a significant proportion of the population. It was hypothesised that, at first, the virulent form of malaria we fear today did not infect humans. During that time, random mutations occurred in the HbS gene. It did not cause any problems nor did it confer any benefits. The parasite, Plasmodium falciparum, which infected only birds, made a jump to humans 10,000 years ago, causing a devastating scourge in human populations. This parasite hitched a ride on the common mosquito and when the mosquito feasted on human blood, got transferred in the blood and started living inside the red blood cells, multiplying, and propagating itself and causing the feared fever and chills in the process.
Since the parasite spends nearly its entire life inside the red cells, it is effectively hidden from the immune system. A very clever parasite indeed! Not only does it have illicit room and board, but it also manages to escape being caught by the immune system cops in circulation (reminiscent of the exploits of Mahakavi Subramanya Bharathi, as depicted in the Thamizh movie
Bharathi, in thwarting the attempts of the cops who arrive incognito in Pondicherry to monitor his activities).
Here is where our HbS enters the picture. It appears that when the mutated form of haemoglobin is mixed with the normal haemoglobin, the parasite doesn’t seem to digest the mutated form as well, starving itself to death. On top of that, the environment inside the cell with the parasite is made conducive for the red cell to sickle. This increases the likelihood of the sickled cells being identified for destruction by the body’s quality control squadron thereby killing the parasites before they become mature. It was thus a marked advantage to have the mutated form of Hb. Thus, the gene for HbS, a defective allele (gene) served a useful purpose, i.e., to protect the carriers of the mutated gene against malaria.
If only the story ended here, it would have been nice. But when two carriers of HbS married and produced an offspring, the double mutant product,
SS, (in 25 per cent of the offspring) turned out to be deleterious. Nature did not intend this, but it arose as an accidental event. A blessing to begin with, indeed, which can turn to a curse if overdone! The real breakthrough in curing SCA is still years away and is vested with gene therapy, whereby one’s defective gene can be complemented with a good gene.
Let us review what causes breast cancer and the remedy made available through biotechnology in our next segment.
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