Gene Therapy


Introduction to Gene Therapy

    Gene therapy, the therapeutic replacement or repair of abnormal genes in human cells, is one of the most promising and controversial innovations in biotechnology. Though gene therapy is possible in the near future for only monogenic diseases (those caused by one gene), the technique holds enormous possibilities in the distant future for correcting more complex diseases.

Gene Therapy Techniques

    There are three main categories of gene therapy techniques. The first, gene insertion, is the only one that is possible in the near future. It involves simply adding the normal version of a defective gene to the genome of the affected cells. When this gene is expressed, it could produce sufficient quantities of a missing or defective protein or enzyme, thus "curing" the disease. This method could potentially be dangerous, however, because a randomly added genetic sequence could disrupt the function of another vital sequence. For this reason, the other two methods are being looked into as ideal future methods of gene therapy.

    The second approach, gene modification, entails the direct chemical modification of of the abnormal DNA sequence in an effort to duplicate the normal sequence in an abnormal cell. This strategy is much less likely to disrupt the function of other genes because no new sequences are introduced.

    The third approach, called gene surgery, is considered to be the ultimate goal of gene therapy. It involves the removal of the precise genetic sequence that is defective, and replacing it with a cloned copy of the normally functioning sequence. This strategy is the least likely to cause unwanted side effects, but it is also the most advanced and therefore is not possible in the near future.

Using the Gene-Insertion Strategy

    There are several different ways of inserting a normal copy of a gene into the defective genome of a cell. All these approaches use vectors, or a "vehicle" used to get foreign DNA sequences into living cells. The most popular vectors are retroviruses, or viruses whose genetic information is encoded in RNA.

Retrovirus Vectors

    A retrovirus works by infecting a host cell, then using the enzyme reverse transcriptase to use its RNA as a template for making DNA which then becomes integrated into the host cell's chromosomal DNA. The virus can then direct the formation of more viruses. The fact that retroviruses integrate their genetic material into that of the host cell makes them ideal for gene therapy, because they efficiently convey gees into the target cell.

    When retroviruses are used as vectors, a scientist removes the viral genes and replaces them with therapeutic genes. The virus then transfers these genes, instead of the virus genes, into the target cell; however, the virus is no longer capable of replicating itself. This technique is simple and possible in the near future; however, it has many limitations. The viruses can only accept a certain amount of base pairs, limiting the size of therapeutic genes to be transferred.In addition, the genetic information is randomly inserted into the host cell's genome, creating the possibility of disrupting the function of vital genes. There also exists a concern that the virus might not be completely "deactivated", and a patient might be inadvertently infected with a viral disease.

Other Insertion Techniques

    Gene therapy that targets blood-cell disorders, such as sickle-cell anemia or inherited immune deficiencies, could be focused on bone-marrow cells known as stem cells. Current techniques for gene therapy of these disorders require new treatments every few months, because the genetically altered blood cells die off. By altering the stem cells, which carry a full genetic complement and give rise to new blood cells to replace those that die, one treatment in a lifetime would be enough. Despite the efforts of scientists, these stem cells remain elusive and difficult to genetically alter.

    Some scientists, concerned about the dangers of using viral vectors, have proposed creating an artificial chromosome and inserting that into target cells. These scientists have suggested coating a manmade chromosome in natural proteins, inserting it into a target cell, and allowing it to express its lifesaving genes.

Gene Therapy Successes

    In 1988, researchers began the first test that would definitively show whether foreign genes, implanted into a human, were as dangerous as some people predicted. Genes for antibiotic resistance were implanted in blood cells called TILs (tumor-infiltrating lymphocytes). These modified cells were then given to a 52-year-old man with malignant melanoma (a fatal skin cancer) which had spread to his liver. He was told he had two months to live.

    The man received the TILs and lived for nearly a year after the treatment in May 1989 - much longer than previously expected. The genetically altered cells were detectable in the man's body up to three months after the injection. Most importantly, this landmark case proved that foreign DNA could be introduced into humans with no adverse effects, and paved the way for more advanced trials in the future.

    The first true gene therapy took place in 1990, with the treatment of two young girls who suffered from ADA (adenosine deaminase) deficiency, a rare type of immune disorder. Victims of the disease have high risk of cancer and are highly vulnerable to infection. In this trial, viral vectors carried ADA genes into white blood cells known as T-cells, which were then released into the girls' bodies. The cells produced the enzyme at about 25% of normal, which is enough to reverse the effects of ADA deficiency. The technique is not perfect - it requires regular infusions of T-cells - but it vastly improved the quality of life for the girls who were the first test subjects.

Future Gene Therapy Candidates

     There are many possible candidate diseases for gene therapy, most of which ar rare, but some of which are fairly common. Diseases targeted for future gene therapy include cystic fibrosis, a disorder of the secretory cells common in Caucasians; sickle-cell anemia, a hemoglobin disorder common in people of African descent; Lesch-Nyhan syndrome, a disease that causes retardation and a self-mutilating tendency; and familial hypercholesterolemia, a disease in which the ability to absorb a type of cholesterol is reduced in carriers and absent in full-blown victims. All these diseases have been researched by biotechnology companies as potential gene therapy candidates. In addition, the possibility of infecting tumor cells with viruses that render such cells vulnerable to destruction by normally harmless chemicals is also being studied.

Somatic Cell vs. Germ Cell Therapy

    All the gene therapy techniques discussed so far have been aimed at somatic, or bodily, cells. These techniques can help individuals with genetic diseases, but do nothing for their offspring. It has been suggested that the same gene therapy techniques applied to somatic cells could be applied to germ cells, or reproductive cells (eggs and sperm),and eliminate certain genetic diseases from the population (with the exception of spontaneous mutation, which is very rare). This possibility has been vehemently opposed by many religious and scientific groups, but is also one of the most attractive applications of gene therapy.

    The idea of removing, say, the gene for Huntington's chorea from the human population doesn't seem like it could possibly be a bad idea. After all, Huntington's chorea is one of the most tragic genetic diseases known to mankind. However, many scientists express a concern that random insertion of replacement genes into germ cells could disrupt vital genes and create a predisposition to cancer in the unborn child. (In this case, a predisposition to cancer seems the lesser of two evils, since Huntington's is fatal to all those who inherit the gene.) Many religious groups also object on moral grounds, saying that life is sacred and should not be tampered with.

    Needless to say, germ-cell therapy needs to be scrupulously tested to guard against causing other diseases or cancer risks in children born of altered cells. Of course, this procedure should be entirely elective, and those who choose not to alter their cells should not be stigmatized in society. Currently, gene-therapy technology is not advanced enough to attempt germ-cell therapy.

A Slippery Slope

    Many people see germ-line gene therapy as the beginning of humanity's descent down a slippery slope. They worry that people with genetic diseases will be stigmatized as "flawed" in a Nazi-style quest for genetic purity. In addition, they wonder if, after genetic diseases are dubbed "flaws", other traits such as nearsightedness, shortness, or athletic and academic inability will also be engineered out of the population. In this scenario, it is possible for parents to choose their child's gender, physical appearance, athletic ability, and academic proficiency.

    This scenario, though unlikely, is extremely dangerous - it could disrupt the gender balance of the population, lead to an extreme loss of genetic diversity, and ultimately even lead to an increase in genetic diseases because so many engineered children possess the same "desirable" genes that inbreeding becomes a problem. Also, by eliminating certain "undesirable" traits (such as sickle-cell trait), we could eliminate important adaptations to certain environments. (Elimination of sickle cell trait would probably lead to an increase in malaria, since it confers natural resistance to the disease.)

Gene Therapy: Ethical Principles

Introduction Screening Cloning Weapons Environmental Issues

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