Chapter 4
Genes and Health

Genes And Health 3036
Photo by: Attila Németh

The discoveries of twentieth-century genetics in general, and the Human Genome Project in particular, have launched medicine on a whole new course. Rather than waiting for diseases to develop and then treating them with drugs or surgery, doctors are now embarked on finding the genetic causes of disease in the hope of fixing the malfunctioning gene before the illness even begins to show its early symptoms. In addition to repairing faulty genes, medical researchers now have within their grasp the ability to analyze individual genomes—the total genetic makeup of specific organisms—to see if they have a full complement of genes and to add healthy versions of those that are missing.


Not all ailments are genetic diseases, but it is becoming increasingly apparent that genes play some role in almost everything that can go wrong with a human being. Defects in genes, or genes that fail to appear altogether, are due to a process called mutation. The concept of mutation covers a wide range of circumstances. "Mutations are alterations in existing genes," says evolutionary biologist Dennis O'Neil. "They can be as small as a point mutation, which is a change in a single DNA condon [three base pairs in a DNA sequence that specify the instructions for making an amino acid] or as large as a major structural modification in chromosomes and even missing or extra chromosomes." 25

Mutations are very common, and not all are debilitating to the carrier. "In order for a mutation to be inherited, it must occur in the genetic material of a sex cell," O'Neil says.

Estimates of the frequency of mutations in human sex cells generally are about one per 10 to 100,000 for any specific gene. Since humans have approximately 32,000 genes, it is to be expected that most sex cells contain at least one mutation of some sort. In other words, mutations are probably common occurrences even in healthy people. Most mutations probably do not confer a significant advantage or disadvantage. They are relatively neutral in their effect. However, some are extremely serious and result in death before birth, when an individual is still in the embryonic or early stages of fetal development. 26

If a mutation occurs in a somatic cell, it will affect only that person in whose body the cell resides. If, however, it occurs in a sex cell—sperm or egg—it will be passed on to the next generation, as O'Neil points out. Mutations occur when DNA replicates itself. The process is extremely complex. The long, twisted DNA molecule straightens out and splits down the center. Each nucleotide (each A, C, T, and G) is separated from its original partner. As the process of replication continues, each of these nucleotide letters gets paired up with a new partner, an A with a T, a C with a G. In order for this to happen, many individual biochemical reactions have to take place. One little slip, and a mutation occurs.

Cells have a way of checking to make sure that replication takes place as it is supposed to, but because thousands of base pairs are involved for each gene, the mechanism occasionally fails. In those cases, a gene is created that does not contain the correct information to produce the proteins that it normally makes. Since proteins produce an organism's traits, a trait will be affected whenever a replication failure happens. Some of these miscues are relatively harmless, but others can lead to the catastrophes we refer to as genetic diseases.

One way to conceptualize this process is to think of the gene as a recipe for an amino acid (amino acids are the building blocks of proteins). Each line of the recipe is a sequence of As, Ts, Cs, and Gs. If a mutation occurs, the letters get out of order and the recipe produces an amino acid other than the intended one. When that amino acid combines with others, either a different protein will result or, in some mismatches, no protein at all will be produced. Depending on the role that protein plays in the functioning of the body, the end of the process may be a disease, perhaps a deadly one.

Genetic Disease

So far, medical scientists have identified almost ten thousand diseases stemming from genetic mutation. As researchers study the information gleaned from the Human Genome Project further, more genetic disease will be discovered. But it is important to realize that not all mutations are bad. In fact, mutations have made evolution possible. "The great diversity of life forms that have been identified in the fossil record is evidence that there has been an accumulation of mutations producing a more or less constant supply of both small and large variations upon which natural selection has operated for billions of years," O'Neil says. "Mutation has been the essential prerequisite for the evolution of life." 27

Scientists cannot yet identify the specific causes of genetic mutation. It is suspected that environmental factors may play a role in some instances of this phenomenon, but most mutations are thought to occur spontaneously. In other words, they happen by chance and there is no way to control them, given the complexity of DNA replication. But, although they cannot be controlled, their effects can be studied because they take the form, most commonly, of abnormalities in the characteristics that make up the organism in which they occur. By tracing the abnormality backward to the cause using genetic linkage maps, scientists have been able to relate certain disease to certain mutations. This is the scientific basis for genetic medicine.

It has become apparent that large genes, simply because they are made up of many base pairs, are more susceptible to mutation than small genes and that most genetic diseases are caused by defects in more than one gene. However, many genetic diseases are the result of a single point mutation (a single-letter misspelling in the genetic code) in a single gene. Sickle-cell anemia, a blood disorder that affects mostly people of African descent, is one such disease. It is so typical of this type of genetic disease that a brief description will provide a good basis for understanding this phenomenon.

Sickle-Cell Anemia

Sickle-cell anemia is not contagious; no one can catch it from another person. The only way to contract the disease is to inherit it from one's parents. It manifests itself as a defect in the shape of red blood cells that interferes with their ability to transport oxygen to other cells in the body. Normal red blood

Elongated red blood cells, pictured here with normal, doughnut-shaped red blood cells, are characteristic of the genetic disease sickle-cell anemia.
Elongated red blood cells, pictured here with normal, doughnut-shaped red blood cells, are characteristic of the genetic disease sickle-cell anemia.
cells are doughnut-shaped. In persons suffering from sickle-cell anemia, the cells are shaped like a half-moon or sickle, hence the disease's name. These sickle-shaped cells are unstable and break apart easily, clogging or damaging blood vessels, leading to pain, lung damage, and, in some cases, heart and brain damage as well.

Sickle-cell anemia is a recessive genetic disease, meaning that to contract it, a child must inherit two defective alleles of the relevant gene, one from each parent. In this way, it is similar to the shortness trait that Gregor Mendel noticed in his pea plants. Recessiveness is one reason why sickle-cell anemia is so insidious. People with only one allele for the disease will show no symptoms and therefore may be unaware that they are carrying the defective gene. It is only when two affected people produce offspring together that sickle-cell anemia occurs.

Sickle-cell anemia was first described in medical literature in 1910, but it was not until 1948 that Nobel Prize–winner Linus Pauling discovered that the hemoglobin, a protein in red blood cells, in people with sickle-cell anemia was different from that in nonsufferers, making sickle-cell anemia the first disease in which an abnormal protein was known to be at fault. Then, in 1956, two British medical researchers, Vernon Ingram and J.A. Hunt, carried out an experiment to sequence the hemoglobin from the blood of a person with sickle cell. They found that an expected amino acid had been replaced by another. Knowing which sequences of As, Ts, Cs, and Gs coded for both proteins, they were able to work backward and discover the genetic mutation responsible. That made sickle-cell anemia the first genetic disorder for which an adequate molecular explanation was known.

"People who inherit two genes for sickle hemoglobin (one from each parent) have sickle cell disease," says Dr. Kenneth R. Bridges.

With a few exceptions, a child can inherit sickle cell disease only if both parents have one gene for sickle cell hemoglobin. . . . [Following Gregor Mendel's ratios for recessive inheritance] a one-in-four chance exists that a child will inherit two normal genes from the parents. A one-in-four chance also exists that a child will inherit two sickle cell genes, and have sickle cell disease. A one-in-two chance exists that the child will inherit a normal gene from one parent and a sickle gene from the other. This would produce the sickle trait. 28

Thus, the basis for understanding genetic disease was laid down by Gregor Mendel when he studied inherited characteristics in garden peas. However, it took a century of work by molecular biologists to relate this discovery to the biochemical processes that govern it. Genetic medicine, and the great hope it has engendered, is the result. In the case of sickle-cell anemia, it is now possible to test prospective parents to see if either or both are carrying the sickle-cell trait, giving them the option of whether to have children who will be subject to the risk of inheriting the disease. "Newborns in most states are tested at birth by hemoglobin electrophoresis that detects sickle cell disease," Bridges says. "Newborn screening assures that children with sickle cell disease will receive proper care. In the past, some children died of complications of their sickle cell disease before the condition was diagnosed." 29

It is now possible to fight sickle-cell anemia on two fronts, neither of which was possible before the advent of genetic medicine. Parents who are carrying the sickle-cell gene can choose not to pass it on to their children, and children who do have the disease can be treated with drug therapy early enough to avoid the most dire consequences of the condition, improving the quality and duration of their lives.

Gene Therapy

Progress has been made in identifying the cause of many other genetic diseases. These discoveries have not, in most cases, yielded a cure. However, further research may one day provide a cure or at least a test that will alert parents that they are likely to pass the defective genes on to their children and give them a chance not to.

Early detection of disease is just one of the ways in which genetics is transforming medicine. And it is one of the more primitive ways. With the completion of the Human Genome Project a whole new field has opened up. Instead of treating disease with medications and/or surgery, scientists hope that genetic disorders can be corrected as soon as they are identified by editing the letters—the As, Ts, Cs, and Gs—that are responsible for the genetic abnormalities that cause the conditions. This field is called gene therapy, and it involves repairing broken genes or adding genes that are missing altogether from an individual's genome.

Adenosine deaminase (ADA) deficiency is the first disease combated with gene therapy. It is a catastrophic disorder of the immune system that always results in death if it is not treated. "Gene therapy for ADA was chosen for the first human gene therapy for several reasons," says biologist Paul Heyman. "It is the result of a mutation in one gene, making it simple to replace. . . . Also, only a small amount of ADA activity is needed for therapy to be effective, while too much ADA does not seem to have a negative effect on humans." 30

The first attempt to treat ADA deficiency with gene therapy was carried out in 1990 by Dr. Michael Blaese on two girls at the National Institutes of Health Center for Human Genome Research in Bethesda, Maryland. Cells were removed from the girls' blood, the deficient copies of the ADA gene were removed using genetic engineering techniques, and healthy versions of the genes were inserted in their place. The genetically altered cells were cultured in a laboratory for several days and injected into the girls' bloodstreams. The therapy continued over two years, and the girls slowly began to show signs of improvement. Today, their bodies produce enough ADA to maintain their immune systems in a satisfactory condition with the help of a supporting drug.

A few years later, Blaese achieved even greater success in the treatment of ADA deficiency, using stem cells—cells at an embryonic stage of development before they differentiate into specialized cells that make up the different kinds of tissue that compose the human body. Blaese and his colleagues "identified three fetuses with inherited abnormal ADA genes," Heyman says. "Upon delivery of the babies, the researchers obtained stem cells from the blood in the umbilical cords of the babies and inserted functional copies of the ADA gene. Four days after birth, the stem cells with the functional ADA gene were inserted into the three babies, who now have normal immune systems." 31 The difference between the two cases is that in the second, no additional drug therapy was needed to maintain the babies' immune systems in a healthy state.

Genetic therapy can also be employed to stop a gene from producing harmful proteins, rather than, as in the cases above, altering or adding a gene to produce a beneficial protein. This procedure is called antisense therapy. Doctors insert a modified gene that stops the defective gene from doing its negative work. Studies are also under way to create genetically engineered artificial chromosomes to combat diseases that are resistant to other forms of genetic treatment.

Ethical Problems

So far, gene therapy has been progressing at a very slow pace. Treatments are being tested for various types of cancer (especially those of the skin, head, and neck), cystic fibrosis, hemophilia, diabetes, Parkinson's disease, and certain forms of heart disease. Advances have been slowed by the difficulty of getting genetically modified genes into target cells and by the complexity of most genetic disease (unlike the two cases discussed above, most of these disorders are caused not by a single defective gene, but by several, thus multiplying the difficulty of designing an effective treatment).

Ethical considerations have also put a brake on research. In 1998, eighteen-year-old Jesse Gelsinger, who was suffering from a liver ailment called ornithine transcarbolzylase deficiency, volunteered to test an experimental gene therapy at the University of Pennsylvania. Soon after modified genes were introduced into his body by means of a virus related to the virus that causes the common cold, his immune system went into overdrive. First, it attacked the virus, then his liver, kidneys, lungs, and brain. Four days later he was dead. The federal government immediately tightened restrictions on human testing of gene therapies, resulting in the cancellation of many promising research projects. Gelsinger's death started an international debate on the ethics of genetic research on humans, and most experts expressed the opinion that more restraint was needed.

Other ethical issues have also held up the application of advances in genetic engineering to medical practice. Stem cells, taken from human embryos before they develop into specialized cells, may someday allow scientists to grow whole replacement organs for transplant purposes. But the most fruitful source of stem cells is embryos that are destroyed when the stem cells are harvested, thus putting this entire area of research into the middle of the abortion debate, one of the most divisive social issues of recent years. The federal administration has chosen to withhold funding for experimental stem cell programs unless researchers agree to use only stem cells cloned from a relatively few already-existing strains. Many scientists question the quality of these cells and maintain that the restrictions will drastically limit advances in this area.

Despite these disappointments, genetic research pioneer W. French Anderson believes that gene therapy

Many scientists believe that stem cells like these could be used to grow organs for transplants. Ethical concerns, however, have slowed the progress of stem cell research.
Many scientists believe that stem cells like these could be used to grow organs for transplants. Ethical concerns, however, have slowed the progress of stem cell research.
will play a crucial role in the future of medicine. "The field of gene therapy has been criticized for promising too much and providing too little," he says.

But gene therapy, like every other major new technology, takes time to develop. Antibiotics, monoclonal antibodies, organ transplants, to name just a few areas of medicine, have taken many years to mature. Major new technologies in every field, such as the manned rocket to the moon, had failures and disappointments. Early hopes are always frustrated by the many incremental steps necessary to produce "success." Gene therapy will succeed with time. And it is important that it does succeed, because no other area of medicine holds as much promise for providing cures for the many devastating diseases that now ravage humankind. 32

User Contributions:

Thank you! This article has helped me so much with my science project, as well I'm sure it will help many people to better comprehend and therefor combat the disese.
it is well organised article,it good for science students especially those doing their project but it lack refrences so try refrencing next time
This is a great article i really enjoyed reading it and have learned alot about genetic diseases
What is the genetic aberration that makes the body stop moving but has to do with the genes and dna of a child that was born with a deffect?
Are you thinking of Tay Sachs disease? This disease affects children usually under 5 years old.

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