Thesis: While gene therapy may pose practical medical benefits for humans, ethical considerations must be addressed in order for society to utilize the potentials of gene therapy appropriately.
Outline
I. Introduction
II. Background Information on Gene Therapy
B. Types
of gene therapy
1. Somatic gene therapy
2. Germ-line gene therapy
C. How
does gene therapy work?
-vectors used to transport genetic DNA into the human genome
D. Development
of gene therapy
1. Ex-vivo somatic cell gene therapy
2. In-sito somatic cell gene therapy
E. Future
of gene therapy
1. Production of a highly efficient gene-delivery system
2. In-vivo somatic cell gene therapy
3. Germ-line gene therapy
III. Ethical Issues of Gene Therapy Lead to Much Controversy
A. Reasons
to allow gene therapy
1. Main arguments for gene therapy in general
2. Arguments for germ-line gene therapy
B. Reasons
against allowing gene therapy
1. Arguments against germ-line gene therapy
2. Genetic discrimination
3. Risks to the patient and offspring
IV. Use of Gene Therapy for Genetic Enhancement
A. Definition
of genetic enhancement
B. Reasons
why genetic enhancement may occur
C. Major
arguments against genetic enhancement
D. Solution
to prevent the misuse of gene therapy for genetic enhancement
V. Conclusion
VI. Works Cited
Gene therapy is a powerful new technology that has the ability to change the way medicine is practiced in the future. The potential of gene therapy offers great hope for cure and alleviation of suffering from genetic disorders that now plague numerous people. Within this past decade, much research has been conducted to learn about the aspects of gene therapy, but there is still much to learn before it is an effective medical treatment. Despite failures to prove any clinical efficacy, many experts of gene therapy predict that the first clinical success will occur in the near future. Gene therapy is a highly controversial topic that entails numerous ethical issues that need to be thoroughly analyzed before it is widely available to the public. While gene therapy may pose practical medical benefits for people, ethical considerations must be addressed in order for society to utilize the potentials of gene therapy appropriately.
Background Information on Gene Therapy
Gene therapy attempts to cure or treat genetic diseases by correcting the genetic errors responsible for it. Genetic diseases can be either inherited diseases such as cystic fibrosis as well as acquired diseases such as cancer ("What is Gene Therapy?"). These diseases are caused by the absence or defective structure of specific genes that change the composition or pattern of proteins expressed by the cell ("What is Gene Therapy?"). Gene therapy attempts to treat these genetic disorders by inserting a normal gene into diseased cells to replace an absent or defective gene or to enhance the production of proteins that are needed to correct or prevent genetic diseases ("What is Gene Therapy?"). Essentially, gene therapy modifies the expression of a person's gene to provide the patients cells with the genetic information necessary to eliminate a genetic disease.
Currently, there are two forms of gene therapy. One type is called somatic gene therapy, which involves the manipulation of gene expression in cells that will be corrective to the patient but not inherited to the next generation. This is the type of gene therapy that is currently being intensely studied in laboratories throughout the world. The other form of gene therapy is called germline gene therapy, which involves the genetic modification of germ cells that will pass the change on to the next generation. Little, if any, research is currently being conducted in germline intervention largely for technical and ethical reasons. However, many advocates of this type predict this will be a realistic option of gene therapy in the future.
When research on gene therapy began, the basic challenge was to develop a technique for delivering genetic material to the cells of the patient. Researchers first learned that gene delivery would not be effective unless the corrective genes were inserted into the nuclei of thousands or millions of diseases cells (Licking 96). When researchers simply injected the genes into the specific tissue where they were needed, no treatment occurred because the genes did reach the cells nuclei (Licking 96). Researchers learned that a therapeutic gene must be delivered by a gene-delivery system or "vector" in order to be inserted into the target cells of the patient's body.
Many of the vectors currently in use are based on attenuated or modified versions of viruses. Over billions of years of evolution, viruses have developed extraordinary ways of targeting and penetrating cells to deliver their DNA into the nuclei of those cells. Researchers learned that nature gave them an unlikely method to deliver genes, and thus formed viruses into vectors by the removal of the disease causing components of the virus and the addition of the recombinant genes that will be therapeutic to the patient (Licking 96). The modified viruses then cannot replicate in the patient but still retain the ability to efficiently deliver genetic material.
The first human trials of gene therapy used a strategy of ex vivo somatic cell gene therapy. In this approach, the patient cells were removed and cultivated in the laboratory and incubated with vectors to modify their genes (Anderson 25). The genetically modified cells were then transplanted into the patient (Anderson 25). The first therapeutic trial that utilized this approach occurred in 1990 and attempted to treat a child with an inherited form of immune deficiency due to being unable to produce a specific protein. The outcome of this trial indicated that gene-therapy eased her symptoms, but it was not yet a cure. Unfortunately, the "gene therapy wasnít very efficient because the number of cells that acquired the corrective gene were too small" (Licking 96). However, this trial proved that the concept of using viral vectors for gene therapy could work, since it did insert some of the corrective genes into the patient's cells and allowed the patient to produce some of the enzyme she previously lacked.
The viral vector used in this first attempt at gene therapy was a retrovirus. These vectors were originally chosen as the most promising gene-transfer vehicle and are currently used in about 60% of all clinical protocols (Anderson 25). Retroviruses have the ability to carry out efficient gene transfer into many types of cells and can provide long term expression of the corrective gene by stably integrating into the host genome of the cell (Anderson 25). They can carry a large amount of DNA and have minimal risk, since they have evolved into relatively non-pathogenic viruses (Licking 96). However, they only infect dividing cells and thus are not useful for cell populations that divide very infrequently or do not divide at all (Anderson 26). They also can disrupt genes and harm the cell because they integrate randomly into the cell DNA (Gregory 88). The vector might insert itself into a tumor suppressor gene, creating the potential for the cell to become cancerous (Gregory 88). Also, the retrovirus can recombine and form into a pathogenic virus, which will be devastating for the patient (Anderson 25). These retroviruses can also cause the body to produce an immune response possibly due to the immune system recognizing the vector as a disease-causing agent (Licking 96). While retroviruses offer some useful applications for gene therapy, they also have some considerable drawbacks that limit the effectiveness of gene therapy.
As gene therapy research evolved, it became apparent that the ex-vivo method of transducing cells was limited and that delivery of genes to organ sites was needed to study a variety of diseases. This lead to the in-sito somatic cell gene therapy, in which the vector is placed directly into the affected tissues (Anderson 25). The viral vector mostly used in this technique is the adenovirus vector. The adenovirus is able to infect cells that do not divide, transduce a large number of different cell types at a very high efficiency, and hold a large amount of DNA (Licking 96). The drawback to this viral vector is that they are not stable in the human genome and thus are not able to produce long term expression of the corrective gene, so repeated administration is required (Licking 96).
Researchers, who had been disappointed with these vectors, devised another vector to deliver genes to cells. This vector, called the adeno-associated virus, is one of the most promising new techniques in gene therapy. Later this year, human-safety trials will be conducted using this type of vector to treat muscular dystrophy and hemophilia (Licking 100). The adeno-associated virus vector has the ability to stably insert itself into the genomes of many different types of cells and avoid the defenses of the human body, possibly because it does not cause disease (Licking 96). However, they can only carry a small amount of DNA and are not able to effectively insert corrective genes into cells that require a large number of genes in each viral particle to achieve transduction (Anderson 28).
Due to the drawbacks of the viral vectors, some researchers have abandoned the viral approach and are instead leaning towards non-viral vectors. Although viral systems are very efficient, two factors indicate that non-viral gene delivery systems will be the preferred choice of the future due to safety and ease of manufacturing. According to W. French Anderson, "A totally synthetic gene-delivery system could be engineered to avoid the danger of producing recombinant virus or other toxic effects produced by biologically active particles" (28). He also believes that manufacturing a synthetic product should be less difficult than the complex methods involved in manufacturing viral vectors (Anderson 28).
Numerous non-viral vectors are now being developed for potential use as a gene-delivery system. Some researchers are developing delivery systems in the form of synthetic compounds such as lipid carriers ("What is Gene Therapy?"). Others are attempting to avoid using delivery systems by injecting naked-DNA into the patient to insert corrective genes (Licking 100). However, these non-viral vectors are not completely effective. They may be much less efficient than viruses at inserting genes into cells and the genes that are inserted may not survive long enough to be of any help to the patient (Licking 100). Other researchers are attempting to overcome these drawbacks by developing artificial chromosomes. Artificial chromosomes have the ability to produce long term function in the cell, but they are inefficient at getting to and inserting the genes into the cells (Licking 100).
Gene therapy has yet to produce a highly efficient gene-delivery system, but experts of gene therapy believe that a safe and efficient gene delivery will occur in the near future. According to W. French Anderson, the "first success of gene therapy will occur within the next five years" (30). At this time of first success, gene therapies goal will be accomplished, which is the production of this highly efficient gene-delivery system. This vector will be one that can be injected, will migrate to specific cells, will result in safe and efficient gene transfer into a sufficient number of those cells, will insert themselves the correct regions of the genome, will be cost-effective to manufacture, and will ultimately cure the disease (Anderson 30).
Along with the production of this vector, the third type of somatic cell gene therapy needs to be developed also in order for gene-therapy to reach clinical efficacy. This third type is in vivo, in which a vector could be injected directly into the blood stream (Anderson 25). According to Anderson, "There are no clinical examples of this third category as yet, but if gene therapy is to fulfill its promise as a therapeutic option, in vivo injectable vectors must be developed" (25). The vectors that can be used in this method are smart vectors that can find their way to certain tissues in the body. This could be achieved by attaching molecules to the vector that recognize specific proteins found on the surface of cells in the target organ (Grace 40).
Some people are claiming that for gene therapy to be effective, the second type of gene therapy, or germ-line gene therapy, must be used. Since 1990, more than 300 clinical protocols have been approved worldwide and over 4,000 patients have had genetically engineered cells added into their body (Anderson 25). The conclusions from these trials imply that gene therapy has the potential to cure numerous genetic diseases and that the procedures appear to have minimal risks to the patient, but the efficiency of gene transfer and the expression of the corrective genes in the human patients is still very low. All of these trials have used somatic cell gene therapy, which has been very difficult due to the problem of getting the genes into enough cells. Advocates of germ-line gene therapy say that this therapy will be much more successful because the procedure will be "infinitely easier" (Taylor 26).
Numerous reasons have been proposed that explain why germ-line gene therapy--the insertion of functioning genes into gametes, zygotes, or preimplantation embryos to treat or prevent an inborn genetic errorówill be much more successful than somatic gene therapy. First, the corrective genes can be added to only one cell, either the gametes or the zygote, thus eliminating the problem of needing to add the gene to numerous cells (Begley 61). Because the genes are added to cells that divide, the cells pass the modified gene to the daughter cells and prevent repeated use of gene therapy. Since all of the cells in the body will have this modified gene, including the cells in the gonads, the gene will be passed along to future generations, thus eliminating the need for them to use gene therapy to cure their genetic disease. Advocates claim that adding the corrective gene to a pre-implantation embryo will be a more efficient method than adding the genes to an adult because the cells in the embryo will absorb the genes better since they are dividing much more rapidly than in adults (Wadman 420). Also, these corrective genes are likely to be passed along to future generations as well since the genes are very likely to reach the gonad cells.
Ethical Issues of Gene Therapy Lead to Much Controversy
While gene therapy poses many potential benefits to treating a vast majority of human diseases, numerous ethical issues need to be considered before further development occurs in this highly controversial technology. A vast majority of these ethical issues stem from germ-line gene therapy and the potential to misuse this technology for enhancement purposes not related to diseases. Other issues need to be considered as well, such as using this technology on relatively healthy people. Gene therapy is a highly controversial topic and there are numerous reasons why people are either for or against it.
The main argument in favor of gene therapy is that it can be used to treat desperately ill patients, or to prevent genetic disorders from occurring in people. Gene therapy poses to cure diseases that conventional medical treatments have failed to treat. For patients that have experienced failure in treating or curing their diseases, gene therapy is their only hope for a future. Gene therapy poses to treat or cure many of these deadly genetic diseases, such as cystic fibrosis, sickle-cell anemia, Huntington disease, hereditary emphysema, hemophilia, cardiovascular disease, muscular dystrophy, and cancer (Palmer and Walters 27-36). Advocates of gene therapy prefer this treatment over other new medical technologies, and argue that the medical community has the obligation to treat patients from these genetic disorders if they have the methods.
Numerous reasons are supported by people who favor the germ-line approach to gene therapy. First of all, curing diseases through the use of germ-line gene therapy is predicted to be more efficient and less costly than repeated somatic gene therapy. Another reason for its use is that it is a moral obligation of health professionals to use this available technology to improve the health of their patient's children and future generations. Also, these supporters feel that people should have the power to prevent their children and future generations from having to undergo somatic gene therapy if they are born with a genetic defect. To further increase the potential of gene therapy, these advocates also feel that researchers in the scientific community should have the freedom to explore new modes of treating or preventing human diseases, which includes germ-line interventions.
Reasons against allowing gene therapy
While there are beneficial reasons that favor germ-line gene therapy, there are also many strong reasons why opponents feel that it should not be available for medical care. Many people do not agree with passing corrective genes onto future generations and manipulating the genes of germ-line interventions in future generations. These opponents disagree with preventing the affected individuals from consenting to interventions in their genome. Another argument against germ-line gene therapy is that it takes away the lives of human embryos to enable others to be deferred from any genetic defects. According to Gerd Richter and Mathew Bacchetta, "the experimental pre-requisites of a technically developed system for germ-line gene correction can only be established by experiments with human embryos that are used up in those experiments" (Bacchetta and Richter 313). Also opponents feel that germ-line gene therapy can affect human evolution and do not agree with humans having the power to "play God" (Gordon 2023). Currently the U.S., unlike European countries, has no laws to forbid any use of germ-line experiments (Wadman 317). These opponents of germ-line gene therapy adamantly want a law that prevents this germ-line intervention from occurring in the future.
Numerous issues arise for opponents wanting to prohibit any further use of gene therapy. One major issue is that they believe that gene therapy might cause genetic discrimination. A practical concern is determining how to ensure equal access to this advanced technology. Those who are unable to afford gene therapy might suffer genetic discrimination. If gene therapy is only available to those who can afford it, "the distribution of desirable biological traits among different socioeconomic and ethnic groups would become badly skewed" ("Human Gene Therapy"). Some people in society will be able to experience the wonderful benefits of gene therapy while others will have to continue to suffer from these horrible genetic illnesses.
Another issue for opposing gene therapy is that undesirable effects can occur to a patient undergoing gene therapy. According to Doris T. Zallen, "There is much that we do not yet know scientifically about gene therapy, because there is much about genes that we do not know" (A64). She gives two reasons why we know so little about gene therapy. First, "scientists know very little about how they act, because a single gene can have multiple effects in different parts of the body" (Zallen A64). Secondly, "genes do not act alone, their effects are manipulated by other genes in ways that scientists have yet to understand" (Zallen A64). Since 1990, most of the thousands of trials on patients since 1990 have been involved in multi-gene disorders (Boyce 20). Multi-gene research may eventually lead to undesirable genetic manipulation of characteristics, such as appearance and personality, which are determined by more than one gene.
When manipulating these genes, critics also believe that negative effects can occur that can be harmful to the patients health. In some cases, these negative effects can lead to death. On September 17, 1999, the first death of a person undergoing gene therapy occurred (Roberts 43). The goal of this clinical trial was to treat or cure the rare liver disease of the patient by injecting the corrective gene through the use of an adenovirus. Unfortunately, the patient died of multiple organ failure soon after the adenovirus vector was injected. This death clearly highlights the fact that these risks can severely harm the patient undergoing the gene therapy. This trial was also highly controversial because it entailed the use of gene therapy on a relatively healthy person who could have done without gene therapy. The patient only had mild symptoms of the disease, and could have lived a healthy life through the use of drugs and a strict diet (Roberts 43). Since there are great risks to the patient, critics believe that gene therapy should only be used on desperately ill people or not at all.
While gene therapy can cause harmful affects to the patient, it can also harmfully affect offspring and future generations. According to Mathew D. Bacchetta Gerd Richter, "any mistake or negative side-effects of genetic germ-line manipulation can be inherited by oneís children and by future generations" (313). The only way to limit these consequences is by negative eugenic means, such as forced sterilization, forced abortion, or restriction of reproduction (Bacchetta and Richter 313). Not only can this occur in germ-line gene therapy, but in somatic gene therapy also. Genetic material that is introduced into a patient may be able to migrate from the cells where it is intended to other locations in the body, including the gonads. According to Neil Boyce, "While scientists have no evidence that a transferred gene has ever spread to sperm or eggs, they have no proof that it will not happen" (21). Thus, these inserted genes can be passed on to children and future generations if the genes find their way into sperm or egg cells. In effect, both the patients and the future offspring can be at risk to the negative effects involved in both types of gene therapy.
Use of Gene Therapy for Genetic Enhancement
Definition of genetic enhancement
Among the numerous ethical issues that surround gene therapy, the one that stands out the most is the possibility of the use of gene therapy for enhancement purposes not related to curing or treating a disease. According to Doris T. Zallen, the definition of genetic enhancement is "the use of genetic engineering to improve the appearance or abilities of healthy individuals" (A64). The technology of gene therapy may someday allow a healthy person to try to modify their genes to bring about changes that the person sees as improvements. This type of gene therapy is the equivalent of cosmetic surgery. Experts of gene therapy have suggested that genetic enhancements could be performed to affect physical characteristics such as size, aging, obesity, hair growth, as well as mental characteristics such as aggressive tendencies, memory, and general cognitive ability (Palmer and Walters 101 -108).
Reasons why genetic enhancement may occur
Valid reasons explain why gene therapy may eventually lead to the genetic enhancement of humans. W. French Anderson states, "The side effects of from gene-therapy protocols have been so minimal, that the danger now exists that genetic engineering may be used for non-disease conditions, that is for functional enhancement or "cosmetic purposes" (29). Due to the minimal side effects of gene therapy through clinical trials, people may be inclined to use gene therapy to enhance their genes. Many experts predict that it will be very difficult to prevent this technology from enhancing their genes. One reason is that companies may initially seek approval for enhancement gene therapies by disguising them as medical treatments. For example, a therapy to improve memory might claim to prevent Alzheimers disease and a therapy to stimulate hair growth in chemotherapy may lead to millions of balding men receiving gene therapy (Boyce 20). Once the Food and Drug Administration licenses a product for some valid medical use, it can be prescribed by doctors for any "off-label use" that is felt by the doctor to be clinically justified (Anderson 29). When doctors begin using this gene therapy for other uses than what it was originally intended for, then before long, gene therapy will include cosmetic treatments.
Another reason for the eventual occurrence of genetic enhancement is that parents may want to use gene therapy to enhance their children. Critics of germ-line gene therapy predict that its use may lead to the "construction of designed human beings" (Bacchetta and Richter 313). Recent polls predict that using germ-line gene therapy for this purpose may occur. One poll found that up to 20% of parents say they see nothing wrong with genetically altering their children to give them an edge over other children (Taylor 25). When this technology becomes available for genetic enhancement, some people predict parents will use it and will convince others to use it also. According to William Gardner, "some parents are likely to find enhancement attractive and be pressured to use it because of the potential advantages for their children" (75).
Major arguments against genetic enhancement
Major arguments against genetic enhancement are that it might reinforce irrational societal prejudices and that it is morally wrong. If genetic enhancement is available, it can provoke "social prejudices against people who are obese, short, or mentally disabled" (Zallen A64). People who could not afford enhancement and those who do not wish to be genetically enhanced eventually might suffer discrimination. The use of gene transfer technology applied to enhancement will certainly lead to a further widening of differences among members of the human species. Not only do people believe that genetic enhancement might cause social prejudices, but they also feel that it is unethical. Many people find using gene therapy for non-disease purposes very troublesome and want society to prevent it from happening (Gordon 2023).
Solution to prevent the misuse of gene therapy for genetic enhancement
The use of genetic enhancement is a destructive use of gene therapy, so guidelines need to be established to prevent the misuse of this technology for this use. Society needs to determine when the use of gene therapy is for a cosmetic purpose or for an illness. Recently, this line between the treatment of disease and the "enhancement" of normal traits is becoming increasingly blurred. For example, human growth hormone treatment was developed for people with an inherited hormone deficiency, but it is now prescribed for short, healthy children to help them grow (Boyce 20). Also, athletes can now increase their performances by taking erythropoietin, a drug that stimulates the production of red blood cells and is usually used to treat anemia (Boyce 20). When deciding who and what will be the candidates for human genetic engineering, a clear line needs to be drawn between whether this treatment will be used for an illness or for cosmetic purposes. The issue of who should receive gene therapy is clear. Those with a severe disease should be the only people eligible for the medical treatments offered by gene therapy (Torres 50). The leading medical societies need to insure that gene therapy is controlled and monitored, by setting up some mechanism between acceptable gene therapy and unacceptable enhancements before genetic enhancement damages our society.
Research on gene therapy has advanced greatly in the past decade, but there has still been no clinical efficacy primarily due to poor delivery systems and gene expression after genes are delivered. However, many geneticists feel that gene therapy will experience its first clinical success soon and live up to its potential to treat and cure many genetic disorders. Before gene therapy is available to the general public, we need to think about the various forms of the arguments for and against gene therapy to better inform our understanding of the issues at stake. Numerous ethical considerations need to be thoroughly analyzed so that society does not misuse its powerful abilities. Gene therapy needs to be closely monitored to prevent the use of genetic enhancement and leading to irrational social prejudices. If society learns to use the abilities of gene therapy appropriately, then its potentials will be of valuable use by offering patients therapeutic genes to treat, cure, and ultimately prevent a wide range of diseases that now plague mankind.
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