Thursday, February 19, 2009

Evolutionary Trade-Offs:Sickle Cell Disease and Malaria


Evolutionary trade-offs in performance from one environment to another have long been thought to be essential in the balance in population and distribution of organisms. It is an essential concept in natural selection. (The process in nature by which, according to Darwin's theory of evolution, only the organisms best adapted to their environment tend to survive and transmit their genetic characteristics in increasing numbers to succeeding generations while those less adapted tend to be eliminated.) An advantageous mutation in a certain environment will increase the likelihood of reaching the age of reproduction, allowing passing on of the gene to the next generation, therefore a positive mutation. If the mutation is detrimental to health and the person dies before reproduction, the mutation is lost and is therefore a negative mutation. Natural selection has to be considered in the context of "pre-modern" societies. Modern medicine has altered the balance of nature and often allows us to rescue people who otherwise would die of their condition, for example, juvenile diabetes; a hereditary disease which used to cause death in childhood. Now due to medical advances it is now possible to treat juvenile diabetes therefore natural selection is no longer a problem. Other than modern medicine, natural selection would suggest that no hereditary disease would be passed on to the next generation. This is in fact not true, this is when evolutionary trade-offs occur, where pros and cons exist for a mutated gene, providing enough advantage to pass on the gene to the next generation.
One evolutionary trade-off which has caused much interest in the medical world of late is the genetic trade-off evolving amongst people who carry genes for sickle cell disease, and the protection they have from malaria.
Malaria is one of the most common infectious diseases, each year, attacking 400 million, in which 3 million develop the illness. The disease is caused by transmission of plasmodium parasite usually by being bitten by an infective female Anopheles mosquito. Only four types of the plasmodium can infect humans, the most dangerous being P.falciparum (the other three being P.vivax, P.ovale, P.malariae).
The plasmodium parasite spends part of its life in the mosquito and part in the human host. The infective plasmodial sporozoites enter the bloodstream from the saliva of the feeding female anopheles mosquito. The Kupfer cells which are part of the reticulo-endothelial system in the liver clear the sporozoites from the blood stream and kill many of the organisms. A fraction of the sporozoites escape destruction however, and penetrate the hepatocytes of the liver where they multiply. The parasite once in the hepatocyte transform into a new entity; schitzonts which replicate vigorously forming merozites which totally fill the hepatocytes. Rupture of the hepatocyte membrane causes a release of merozoites into the bloodstream where they invade circulating erythrocytes where they assume a ring form called trophozoites. These organisms consume haemoglobin, enlarge and metamorph into schizonts and merozoites. Eventually the erythrocytes lyse and release merozoites that can penetrate new erythrocytes. Trophozoites can also form gametocytes in the erythrocytes which is the sexual form of the parasite which stay in the red cell. Transmission of the parasite into a feeding mosquito occurs when these gametocytes are taken in. The sexual reproduction cycle then begins in the mosquito, which subsequently leads to human transmission.
There are many points in the life cycle where the parasite could be targeted for destruction. Firstly the antibodies and lymphocytes called ‘natural killer cells’ attacking the sporozites when first injected into the blood stream. Prior exposure to the parasite would cause a stronger more effective immune attack due to conditioned lymphocytes. Another point is the intrahepatic phase of malaria. Potentially a mutation to the structure and function of hepatic cells that could kill the parasite or slow its growth would prove effective, although none is known. The last phase of the parasite’s life cycle that the body could attack is at the red cell invasion and multiplication phase; where a mutation could destroy infected cells and parasites allowing replacement by non-infected red blood cells which would potentially eliminate the malaria parasite. At this phase the mutated sickle haemoglobin (haemoglobin S) proves effective in impairing malaria growth and development when it is in its heterozygous state.
Sickle cell trait provides a survival advantage over people with normal haemoglobin in regions where malaria is endemic for example in West Africa. The first signs of the relationship between carriers of the mutant hemoglobin S and their protection against malaria, was determined due to the realization that the geographical distribution of the gene for haemoglobin S and the distribution of malaria in Africa virtually overlap. Sickle haemoglobin provides the best example of a change in the haemoglobin molecule that impairs malaria growth and development.
The mechanism in which it does this is unsure, but there are many circulating ideas.
In 1970 it was suggested by Luzzatto, et al that it was due to low oxygen tensions causing cells with the haemoglobin S to sickle. When the erythrocyte is then infected by the parasite P.falciparum it deforms due to its high metabolic rate therefore reducing the oxygen tension within the erythrocytes. Deformation of sickle trait erythrocytes would mark these cells as abnormal and then be removed from the circulation and then destroyed in the reticuloendothelial system by macrophages.
Others suggest that malaria parasite could be damaged or killed directly in sickle trait erythrocytes impairing on its proliferation. Ultrastructural studies showed extensive vacuole formation in P. falciparum parasites inhabiting sickle trait red cells that were incubated at low oxygen tension, suggesting metabolic damage to the parasites (Friedman, 1979).
Other investigations suggest that oxygen radical formation in sickle trait erythrocytes retards growth and even kills the P. falciparum parasite (Anastasi, 1984). Sickle trait red cells produce higher levels of the superoxide anion (O2-) and hydrogen peroxide (H2O2) than do normal erythrocytes. Each compound is toxic to a number of pathogens, including malarial parasites.
Sickle cell disease in its homozygous form can prove fatal, and it is likely that a person suffering will not reach the age of reproduction, therefore the genes will not be passed on, and its advantage in protection against malaria will not be seen. This means that negative selection exists for sickle cell disease. However it takes two copies of the mutant gene, to give someone the full-blown disease. Heterozygote carrying one mutant allele and another normal (sickle cell trait) will see a heterozygous advantage, because of the protection against malaria. This advantage is known as a balanced polymorphism where the heterozygote for two alleles of a gene has an advantage over either of the homozygous forms. However this does allow transmission of the mutant gene. Two heterozygote states for the allele mating would introduce a possibility to reproduce an offspring with the disease. The survival rates of the heterozygote state will be greater than the homozygote form, therefore increasing the chances of an affected offspring.
Increasing knowledge in evolutionary trade-offs that occur in pathogens have been used as the basis of new medical treatments. One example of an evolutionary trade-off that is the basis of a form of treatment for the disease is HIV. Human immunodeficiency virus is one of the fastest evolving entities known, making it very difficult to treat. Resistant strains of the HIV evolve when exposed to antiretroviral drugs, due to accumulating lots of mutations during reproduction. However, gaining the advantage of growing resistance to antiretroviral drugs, does come with its negative effects. If you place a resistant and non-resistant organism in head-to-head competition in the absence of the pesticide or drug, the non-resistant organisms generally wins. This theory is the basis of a new dosage regime for the drug.
If a patient has developed a resistant strand of virus to a drug, then the patient stops taking the drug, evolution theory suggests that the viral load will evolve back to a non-resistant strain due to natural selection. If the patient then takes a very strong dose of the same drug, it could effectively retard the replication of those non-resistant viruses, reducing the viral load to very low levels.
This therapy has shown early, promising results, although its efficacy is low and it may not eliminate HIV, but it could slow down the progression of the disease. The treatment however has laid a grounding for more research, and proves that we can impinge on these evolutionary trade-offs and take advantage of them in medical treatment.

4 comments:

  1. AFAIK this same approach is also tested as a treatment in cases of multiple resistance against antibiotics. First "select" bacteria which are resistant against a certain combination of antibiotics, than treat with a different antibiotic that targets a "weakness" (which is the result of a trade-off) that is connected with resistance to this antibiotics.

    There're a lot of examples regarding trade-offs if you look at immunology. Your major histocompatibility type (in humans called HLA (human leukocyte antigen) type) can determine your susceptibility to certain diseases.

    It is proposed that it is advantageous for a population to have a high MHC diversity because that ensures that at least some individuals in a population do have a resistance to certain diseases and it has been proposed that the MHC type is even influencing mate choice - the more diverse, the better.
    So, the same MHC type can be protective against infection with one class of germs but OTOH makes you more susceptible for another kind of disease.

    Antoher example of immunology-related trade-offs is the CCR5 mutation that provides protection against HIV infection: "The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory to not associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,[7] indicating that not all of the functions of CCR5 may be compensated by other receptors."
    In this case, lower risk of being affected by HIV and small pox is coupled with a higher risk of getting affected by West nile virus (and of course, possibly other viruses as well).

    All the best,
    Sabine aka JLT

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  2. It is amazing how viruses evolve to the extent that they are indestructible for us ... in a ocacion saw a documentary called buy cialis
    and talked about how medicine is moving to eliminate bacteria and viruses that are resistant to antibiotics even so .. we could not remove them ..... thanks!

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