Gene Therapy

I

Introduction

Gene Therapy, experimental medical treatment that manipulates a gene or genes within cells in order to produce proteins that change the function of those cells. Gene therapy originated in efforts to treat and cure some of the more than 9,000 known genetic disorders, most of which lack an effective therapy. In the United States 1 infant in every 28 is born with a disorder caused by a defect in 1 or more of the estimated 31,000 genes found in the human body. Thousands of children and adolescents die from these diseases each year, and tens of thousands suffer lifelong disability. Although gene therapy is not an approved medical therapy to treat disease, over 400 clinical trials, experiments testing the safety and efficacy of this method on humans, have been conducted in the United States. Scientists expect that within the first decades of the 21st century, gene therapy will offer unprecedented opportunities to treat, cure, and ultimately prevent a vast range of diseases.

The original goal of gene therapy was to substitute a healthy gene for a defective one, or to repair a faulty gene, thereby eliminating symptoms of disease. But researchers have moved beyond inherited genetic disorders to treat other kinds of diseases. Today, nearly 75 percent of all clinical trials involving gene therapy are aimed at treatments for cancer and acquired immunodeficiency syndrome (AIDS). Cancer begins in genes and may be caused by an inherited defect or a mutation (permanent alteration to a gene) that causes a cell to malfunction. AIDS is caused by a virus that disrupts the genetic material of immune cells. Other new gene therapy projects are targeted at conditions such as heart disease, diabetes mellitus, arthritis, and Alzheimer's disease, all of which involve genetic susceptibility to illness. Gene therapists hope to reduce or eliminate this susceptibility. Eventually, gene therapy might help older people to regain strength in withered muscles and density in thinned bones, and to increase pumping power in their aging hearts. Some researchers predict that in the distant future the technology could be used to eliminate genetic defects from families or even to produce “designer babies” with more muscle strength, higher intelligence, sweeter dispositions, or whatever traits parents desire.

Although gene therapy offers seemingly limitless possibilities, researchers have been thwarted by many technical problems. There has only been one successful clinical trial using gene therapy—in April 2000 French researchers reported the successful use of gene therapy to treat two female infants with severe combined immunodeficiency disease (SCID), a deadly inherited disease that impairs the immune system. But even this success was marred when each child later developed a rare leukemia-like illness, thought to be a result of gene therapy. Most clinical trials of gene therapy have not resulted in enough improvement in the patient’s underlying condition to consider it an unqualified success and to justify treating large numbers of people. The extraordinary potential of gene therapy has also raised alarms among critics who warn that the technology could go too far. They note, for example, that gene therapy could offer wealthy families opportunities for genetic enhancement unavailable to the poor. More troubling still for some critics is gene therapy's potential to narrow the human gene pool, producing unknown, and possibly harmful, consequences.

II

The Nature of Genes

A gene is a long segment of the molecule deoxyribonucleic acid (DNA). This segment, composed of minute subunits called nucleotide bases, serves as the blueprint for manufacturing a single protein or enzyme needed for the structure or function of cells. In humans, genes are compressed and bundled into a set of 23 pairs of chromosomes, which stabilize and protect the DNA. Even a tiny error in the arrangement of a gene's nucleotide bases can lead to the production of a protein or enzyme that works improperly, disrupting cellular biology like a broken piston would wreak havoc in an automobile engine. Or the needed compounds might not be produced at all.

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Biologists have known about the importance of genes since the pioneering work of Austrian monk Gregor Mendel. In a series of experiments beginning in the 1850s Mendel showed that the traits of plants are inherited in a precise, predictable manner. But little was known about the physical nature of genes until the 1950s when American biochemist James Watson and British biophysicist Francis Crick developed their revolutionary model of DNA. Watson and Crick showed that DNA is composed of two strands of nucleotides, linked to form a chain and arranged in a structure resembling a twisted ladder, called a double helix. Another key breakthrough came in the early 1970s when researchers discovered a series of enzymes that made it possible to snip apart genes at predetermined sites along a molecule of DNA, then glue them back together in a reproducible manner. These genetic advances set the stage for the emergence of the genetic engineering industry, which has produced new drugs, antibodies, and a host of other naturally occurring chemicals. The discoveries also enabled scientists to contemplate gene therapy.

III

Types of Gene Therapy

There are two distinctly different types of gene therapy: somatic-cell therapy and germ-line therapy. In somatic-cell therapy, gene surgeons attempt to fix genetic malfunctions in somatic (body) cells, such as blood cells and skin cells. This type of gene therapy is the only one that has been performed on humans. Genetic alterations to somatic cells are restricted to the person being treated and cannot be passed on to his or her offspring.

In germ-line therapy, genetic alterations are made to germ cells, such as sperm and eggs, in order to treat inherited diseases. Germ-line therapy is highly controversial because such changes would alter the genetic endowment of the unborn and could be passed on to future generations. Germ-line experiments with laboratory animals have been performed since the late 1980s. In countries that regulate gene therapy in clinical trials, germ-line therapy has yet to be applied to humans. Nevertheless, U.S. researchers have submitted proposals to conduct human germ-line experiments, and many experts predict the first of these experiments will occur early in the 21st century.

IV

Methods

In gene therapy, one or more genes are inserted into a cell, where they produce a missing protein or enzyme. Researchers have developed several methods for transporting genes into cells. The most common technique is to attach healthy genes to genetically modified viruses. These infectious agents, known as vectors, carry the genes into a cell’s nucleus and incorporate them into the genetic material of the infected cell. Another gene-delivery method still under development is chimeraplasty, in which segments of DNA are inserted into a cell’s nucleus. The DNA segment binds with a defective gene in a way that helps the cell’s repair mechanisms identify and fix the defective gene.