Molecular Diseases

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Molecular Diseases

 

  

STAR SCIENCE By A. Padlan, PhD and Gisela P. Padilla-Concep...

 (The Philippine Star) Updated March 04, 2010

Sixty years ago, Linus ing, 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. ing 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. ing 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 s 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.) Mutation s 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 ing, 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. "

 

* * *

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

epadlanupmsi (DOT) ph.

 

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 gpconcepcion@ gmail.com.

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