2016-03-27 10:29:38
I won’t reveal anything new when I say that hemoglobin is the protein contained in red blood cells responsible for capturing oxygen in the lungs and transporting it to the body’s tissues. Hemoglobin multiplies the oxygen-carrying capacity of the blood by seven, making it vital for animals as large as whales to have oxygen available to all parts of their bodies.
Perhaps less well known is the fact that hemoglobin is formed by the union of four protein chains produced by different genes. These molecules are called hemoglobin subunits. We have, first of all, the alpha protein chain, of which hemoglobin has two subunits. These two are joined by two other subunits of the chain called beta. Thus, hemoglobin is an alpha2-beta2 tetramer (from the Greek: four units).
Probably even less well known is that fetal hemoglobin is different from adult hemoglobin. The hemoglobin of the developing fetus is also made up of four subunits, but the two alpha subunits are joined by two subunits of another protein chain, produced by a different gene, called the gamma chain. Fetal hemoglobin is an alpha2-gamma2 tetramer.
Why does this happen? Why can’t fetal hemoglobin be the same as adult?
The reason is easy to understand. As we know, the fetus does not breathe air, being inside the uterus and bathed in amniotic fluid, and must obtain the oxygen it needs from the mother’s blood. For this reason, the fetus needs a hemoglobin that attracts oxygen more strongly than the mother’s hemoglobin. Only in this way can the fetal hemoglobin “steal” oxygen from the mother’s hemoglobin and keep it for transport to the growing organs.
After birth, however, fetal hemoglobin becomes a problem. The increased oxygen needs due to movement mean that this hemoglobin, which strongly binds oxygen captured in the lungs, does not now give it up to cells that need it with due diligence. Fetal hemoglobin is not adapted to the needs of extrauterine life.
Fortunately, throughout evolution, Nature has been learning until reaching the high degree of wisdom that it possesses today. This wisdom causes organisms to “turn off” the gene that produces the gamma chain of fetal hemoglobin and “turn on” the gene that produces the beta chain: fetal hemoglobin disappears from the circulation and adult hemoglobin appears, which, since it attracts oxygen with less force –although still with the necessary force–, once it is captured in the lungs it releases it more easily to the tissues and organs.
mutations
However, in some cases, the newborn may carry deleterious mutations in the genes that produce the beta chain of hemoglobin, which will lead to the production of faulty hemoglobin that cannot adequately carry oxygen, leading to the symptoms of anemia. The so-called hemoglobinopathies, in medical language, occur. For example, a particular mutation in the gene for the beta chain of hemoglobin causes so-called sickle cell anemia, characterized by the fact that defective hemoglobin deforms red blood cells, giving them a sickle-like appearance (hence sickle cell). These red blood cells are destroyed more quickly by the spleen and liver, leading to anemia, as well as other serious problems due to capillary occlusion.
Other diseases caused by defects in the genes of the hemoglobin chains are the so-called thalassemias or “anemias of the sea” (word derived from “Thalassa”, goddess of the sea from Greek mythology, because thalassemias are common in Mediterranean countries ). The most common of the thalassemias is also the one that results from mutations in the genes of the beta chain of hemoglobin, for which reason it is called beta thalassemia. It is estimated that around 80 million people carry a mutation that could cause beta thalassemia if it is inherited from both parents.
In the case of these patients, an increase in the presence of fetal hemoglobin in their blood has been detected. It is as if the body were trying to survive by producing a hemoglobin that works better than adult mutated hemoglobin, even if it does not work optimally.
These insights indicate that some anemias and thalassemias could be treated by “turning on” the fetal hemoglobin gamma genes, which are turned off after birth. The problem is that we do not know with certainty by what molecular mechanism these genes are turned off, which is necessary to be able to intervene on it, reversing it in the case of these patients.
Now, a group of researchers, led by Dr. Takahiro Maeda, from Harvard University, discover that a protein, called LRF, belonging to the family of transcription factors, that is, proteins that regulate the functioning of the DNA to produce all the proteins that cells need, is one of the main responsible for turning off the hemoglobin gamma chain gene. These results have been published in the latest issue of the prestigious journal Science.
This discovery will allow the development of new drugs that prevent the activity of LRF, which will lead to the production of fetal hemoglobin in those adults lacking a normal beta chain of hemoglobin. Let us hope that this hope will soon become a reality.
Referencia: Masuda, T. et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 15 january 2016 • Vol 351 Issue 6270 pp. 285.
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