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miércoles, 24 de marzo de 2010

Molecular diseases

Molecular diseases
STAR SCIENCE By Eduardo A. Padlan, PhD and Gisela P. Padilla-Concepcion, PhD
 (The Philippine Star) Updated March 04, 2010

Sixty years ago, Linus Pauling, in a landmark paper published in Science with several colleagues, proposed the concept of molecular disease. The idea that a disease may be caused by a defect in a molecule was a departure from common belief at that time. Pauling specifically focused on sickle-cell anemia, in which red blood cells became deformed from the normal disk-shape to a sickle-like shape (thus the name) and became stiff (no longer pliable) so that they could no longer easily squeeze through narrow blood vessels (capillaries and venules). The resulting blockages caused inflammations, severe pain, infections, organ damage, and early death. Pauling proposed that the disease was caused by a defect in the hemoglobin molecule.

Experiments showed that sickle-cell hemoglobin, under the influence of an electric field, moved at a speed different from normal hemoglobin, indicating that indeed there was a difference between the two. Subsequent sequence analysis then showed that the beta chain of sickle-cell hemoglobin differs from the beta chain of normal hemoglobin at position 6, where sickle-cell hemoglobin has the amino acid valine, while normal hemoglobin has glutamic acid. (The hemoglobin in red blood cells is made up of four chains identical in pairs: two alpha chains and two beta chains.) There were no other differences.

It was also observed that sickle-cell hemoglobin formed long bundles of fibers, or rods — but only when the molecule is deoxygenated. (The hemoglobin in blood binds oxygen reversibly and functions as an oxygen transporter. It picks up oxygen from the lungs

(becomes oxygenated) and delivers the oxygen to the tissues (becomes deoxygenated).) It is those rods which cause the deformation and stiffening of the red blood cells. Three-dimensional structure analysis of deoxygenated sickle-cell hemoglobin by Warner Love's group at Johns Hopkins revealed that the valine at position 6 fortuitously fits in a hydrophobic pocket of a nearby molecule and this (unfortunate) situation caused the formation of the rods. The glutamic acid in normal hemoglobin, being charged, would not bind in the pocket. Further, the binding could occur only when the molecule is deoxygenated. (The hemoglobin molecule changes shape when going from the oxygenated to the deoxygenated state.) Sickle-cell anemia was clearly a molecular disease.

Since then, many more diseases have been found to have a molecular cause and a molecular disease became known as one in which the pathogenesis (how the disease comes about and manifests itself) can be traced to a single critical molecule, usually a protein. The protein is either produced defectively (like hemoglobin in sickle-cell anemia), not produced at all, or produced in abnormal (reduced or elevated) amounts. There is a disease called alpha Thalassemia major which affects mostly Southeast Asians, Chinese and Filipinos. It is severe and results in death before or soon after birth. It is caused by the complete absence of the gene that produces the alpha chain of hemoglobin.

The ultimate cause of molecular disease is genetic — faulty genes, and the fault could be simply a single nucleotide variation from the normal. The fault could be a mutation in the gene that codes for the particular protein, as in sickle-cell anemia, or it could be the complete absence of the gene itself, as in alpha Thalassemia major. The fault could be in the gene that controls the expression of a particular protein, or in the gene for a protein that modulates the activity of that protein. The defect could be in only one copy of a gene (we inherit two copies — one from our mother, one from our father), or in both copies. Or the disease could be caused by an unusual number (e.g., duplication) of a particular gene, or chromosome. Defects in the genes that control a protein's expression or activity result in abnormal amounts of the active protein.

For example, a type of severe combined immunodeficiency (SCID) has been found to be caused by a defective enzyme, adenosine deaminase. The result of this defect is the inadequate production of lymphocytes that are crucial elements in our immune system. Thus, individuals suffering from SCID are unable to fight infections and have to live in sterile environments, e.g. bubbles, to remain alive.

Another example is Hunter syndrome, which results from the absence or inadequate production of a crucial enzyme, iduronate-2-sulfatase. The gene responsible for the disease is found in the X chromosome. Females, who have two copies of the X chromosome, will not be affected if the defect occurs in only one of the chromosomes. Males, who have only one copy of the X chromosome, are not so lucky.

In our country, geneticists at the Institute of Human Genetics in UP Manila are studying the occurrence of Thalassemias and sickle-cell anemia in the Philippine population. Also at UP Manila, a newborn (babies) screening center to test for treatable genetic diseases has been operating for many years. There are tests for endocrinologic (hormone-related) and metabolic (carbohydrate and amino acid) disorders or inborn errors. By the Newborn Screening Program Act of 2004 (Republic Act 9288), this service has been available to a network of hospitals, lying-ins, and Rural Health Units and Health Centers (RHUHCs) nationwide with cooperation from the DOH. 

How can testing newborns help? Take for example, phenylketonuria (PKU), an inborn error of amino acid metabolism. If a baby has a genetic disorder that leads to low levels of phenyl hydroxylase, the enzyme that converts the amino acid phenylalanine to the amino acid tyrosine, a diet low in phenylalanine and high in tyrosine will solve the problem. If the diet is not adjusted early, phenylalanine from a normal diet accumulates and is converted to phenyl pyruvate (a phenyl ketone, thus the name phenylketonuria), which causes problems with brain development, and leads to progressive mental retardation and seizures.

Are cancer, diabetes, and cardiovascular disease (CVD) molecular diseases? Yes, they are too, in a fundamental and general sense. But they involve defects in more than one critical molecule. Cancer is considered a polygenic disease (with mutations occurring progressively in many genes and proteins); increased risk for diabetes type 2 and CVD is associated with "metabolic syndrome" (with defects involving several interrelated metabolic pathways), and all three are considered complex diseases [complex, meaning with many defects, as opposed to one defect (the original or strict definition of a molecular disease)].

Are molecular diseases always inherited from the genes of either one of our parents? Based on the new wider definition of molecular diseases — no, some mutations can be acquired in one's lifetime. We live in an environment that can cause mutations to our genes through the air and sunlight, our food and drink, and through certain stressful physiologic conditions in our body. Some mutations are inherited, while some are sporadically acquired.

In some cases, the genetic defect does not immediately cause disease, but leads to the propensity for disease. An example is the susceptibility to cancer that has been traced to a defect in p53, a tumor suppressor protein. (p53 binds to DNA and this results in the production of a protein that is involved in the suppression of cell growth. A mutation in p53, that causes it to no longer bind DNA effectively, results in uncontrolled cell growth and to tumor formation.) Mutations in other tumor suppressor genes, like the BRCA1 (breast cancer 1) and BRCA2 genes, have been correlated with higher incidence of cancer. Is the mutation found in a tumor mass inherited or sporadic? One can easily find out. If the mutation is found only in the tumor cells and not in the person's normal cells, it is a sporadic one.

Even some personality disorders appear to have a genetic cause. For example, there is a recent report that the tendency toward pair-bonding, or monogamy, seems to be associated with the number of copies of a particular gene variant (allele) that a person has. Surprisingly (maybe not), the association is found only in males. Men with two copies of the allele are more likely not to form long-term bonds with their partners.

In reality, all diseases are molecular. Effective treatments

require molecular medicine, and disease prevention and diagnosis require molecular analysis. Nowadays, medical doctors and biomedical scientists are focused on the understanding of the molecular basis of diseases. It all goes back to Linus Pauling, that most intuitive, quintessential molecular scientist, one of the greatest scientific minds of our time, who first pointed out molecular diseases. He also said that "man is simply a collection of molecules" and "can be understood in terms of molecules."

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Eduardo A. Padlan is a corresponding member of the NAST and is an adjunct professor in the UP Marine Science Institute. He can be reached at

Gisela P. Padilla-Concepcion is a member of the NAST and is a professor in the UP Marine Science Institute and chairs the Dean's Office on Special Initiatives for the Advancement of the Sciences, College of Science, UP Diliman. She can be reached at

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