Inherited Disorder Ornithine Transcarbamylase Deficiency Biology Essay


In the fall of 1999, the death of Jesse Gelsinger stunned the medical research world and set back gene therapy for years. During the summer of 1999 in Tucson, Arizona, 17 year old Jesse Gelsinger heard about an experiment in gene therapy at the University of Pennsylvania for his inherited disorder, ornithine transcarbamylase deficiency (OTC).

OTC is a genetic disease where the liver fails to properly cleanse the blood of ammonia, a chemical produced in normal metabolism, resulting in toxic levels of ammonia. Many OTC newborns die around birth and half don't make it to age 5.

A regimen of drugs and diet originated by Penn researcher Mark Batshaw enabled Jesse to live to be a teenager. But without a cure, he would eventually die young of his disease.

The son of a handyman, Jesse worked as clerk in a grocery store and rode a motorcycle on weekends, as did his father, Paul. A friend said Jesse "wanted to prove he was a man as much as anything. Penn researchers' claim Jesse was informed that the experiment wouldn't help him, but that it might lead to a cure for OTC babies. His father testified at a later congressional hearing that Jesse's motives had been pure: "He was going to help save lives."

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Jesse's death was unusual because he entered the study, in the parlance of the research, as a "healthy research volunteer." But why weren't studies done on dying OTC patients, as in usually done with potentially lethal, risky experiments? First, researcher James Wilson denied that the experiment could have been expected to kill Jesse. Second, OTC babies are essentially born dying; most babies die within days. It would be hard to prove that any genetic therapy did any good. Third, an emphasized by Penn's own bioethicist Arthur Caplan, parents of OTC babies are so desperate that they would consents to almost any study.

So researchers now made the fateful decision to seek adults with OTC whose livers were still functioning well and to inject an adenovirus into them that contained copies of the gene lacking the OTC patients.

What actually happened was quite grim. Four days after scientists infused trillions of genetically engineered viruses into Jesse Gelsinger's liver part of a novel gene therapy experiment, the 18 year old lay dying in a hospital bed at the University of Pennsylvania. His liver had failed, and the teenager's blood was thickening like jelly and clogging key vessels while his kidneys, brain, and other organs shut down. According to the factual summary of the case, drawn from medical reports in a wrongful death lawsuit, when the physician injected Jesse with the virus, "he suffered a chain reaction including jaundice, a blood-clotting disorder, kidney failure and brain death (Hayes)."

After reviewing this case many ethical questions arise, whose lives should be risked in the name of research? What is a fair amount of danger for a research subject to be subjected to? Although, genetic engineering as well as other scientific methods can enhance the lives of the human species, no one is sure to the repercussions of its actions. Because of this it is unethical and immoral to test these procedures on this generation or generations to come. Many arguments have been made is support of each side of this issue, but in coming to a conclusion about any idea one must weigh the good and the bad effects of each argument. Before one can analysis the process of genetic engineering one must first understand genes.

"Genes are strings of chemicals that help create the proteins that make up your body. Genes are found in long coiled chains called chromosomes. They are located in the nuclei of the cell in your body (" "Genes are made of definite sequences of bases on the DNA chain which code for the production of particular protein. Proteins are chemical substances which mediate the form and function of cells and organisms either by forming part of definite structures or by acting as biological catalysis in living processes. When genes are altered so that the encoded proteins are unable to carry out their normal functions, genetic disorders can result (" Since one should be aware that genetics is the study of genes one could begin to imagine how genetic engineering really works. According to a beginner's guide to genetic engineering, this is the process of genetic engineering "The DNA that one wants to recombine with other DNA in the organism of interest has first to be extracted form the cell of the organism. If there is insufficient extracted DNA for further manipulation it can be exactly copied and thus reproduced in the test tube exploiting the property of bases in the two complementary strands of the DNA helix to pair with each other in a precise way. Finding the gene or DNA sequence of intersect in an organism's DNA is a bit like trying to find a needle in a haystack. The DNA has to be got into some form where it can be 'filed', catalogued and retrieved at will in sufficient quantities for further work. A convenient way of doing this is to clone the DNA in microorganisms such as yeast or bacteria thus creating living 'libraries' of DNA. The procedure exploits the normal reproductive properties of the microorganism, such as transformation and transduction in bacteria (" Gene therapy is a technique for correcting defective genes responsible for disease development. Researchers may use one of several approaches for correcting faulty genes: A normal gene may be inserted into a non specific location within the genome to replace a nonfunctional gene. This approach is most common; an abnormal gene could be swapped for a normal gene through homologous recombination; the abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function; the regulation (the degree to which a gene is turned on or off) of a particular gene could be altered ( Now that one understands what gene therapy is let's discuss how it works.

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In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal", disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common vector is a virus that has been genetically altered to carry normal human DNA. Some of the different types of viruses used as gene therapy vectors: Retroviruses-A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus; Adenoviruses- A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus; Adeno-associated viruses- A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19; Herpes simplex viruses- A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores. Besides virus-mediated gene-delivery systems, there are several nonviral options for gene delivery. The simplest method is the direct introduction of therapeutic DNA into target cells. This approach is limited in its application because it can be used only with certain tissues and requires large amounts of DNA. Another nonviral approach involves the creation of an artificial lipid sphere with an aqueous core. The liposome, which carries the therapeutic DNA, is capable of passing the DNA through the target cell's membrane. Researchers also are experimenting with introducing a 47th (artificial human) chromosome into target cells. This chromosome would exist autonomously alongside the standard 46 ( Since one understands how gene therapy works, one could review the disadvantages of this method.

One disadvantage is immune response. Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk. Furthermore, the immune system's enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients. Another problem with gene therapy is its short-lived nature. Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy. An additional problem occurs with viral vectors. Viruses while the carrier of choice in most gene therapy studies; present a variety of potential problems to the patient, toxicity, immune and inflammatory response, and gene control and targeting issues. Additionally, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease. Another disadvantage involves multigene disorders. Conditions or disorders that arise from mutation in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as hearth disease, high blood pressure, and diabetes are caused by the combined effects of variations in many genes. Multigene or multifactor disorders such as these would be especially difficult to treat effectively using gene therapy ( Finally, gene therapy creates a chance of inducing a tumor. If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor ( There are always advantages along with disadvantages.

"The advantage of the technique is to give someone that is born with a genetic disease or who develops cancer the chance at a normal life (" An additional advantage of gene therapy is longevity, "The fact that society spends so much time educating and training people who later die off and take all their knowledge and experience with them imposes a tremendously hidden cost on society as a whole (" Another advantage is gene therapy provides treatment of a genetic disease at the root of the problem, at the DNA level. Further, gene therapy has the potential to treat a disease for which no treatment is currently available. Next, gene therapy has the potential for life-long treatment from a single injection. Another, advantage is the patients own body produces the therapeutic gene product. For example, the gene that produces human insulin can be inserted into the genome of a bacterium, causing the bacterium to make human insulin. Then there is treatment for one genetic disease has been developed, similar disease should be equally treatable, using a different disease-specific gene ( Finally, gene therapy has brought about the production of medicines in mass qualities. The medicines are pure and much cheaper if technology allows it to be produced in large amounts. These advantages could help in the battle against diseases, but at what cost.

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One of the most common arguments against gene therapy is the slippery slope argument which states, once society begins to change rules, the society may loss control of the rule. If one says it is alright to use genetic engineering for use of therapeutic purposes later on down the road it may be ok to us genetic enhancement, then who knows where else it will lead. According to the article "Human Gene Therapy", "Many persons who voice concerns about somatic cell gene therapy use a "slippery slope" argument against it. They wonder whether it is possible to distinguish between "good" and "bad" uses of the gene modification techniques, and whether the potential for harmful abuse of the technology should keep us form developing more techniques ( Gene therapy violates the Prima facie duty of nonmalefilence, which indicates one must not hurt others. It could be determined that the disadvantages/harmful effects of this process includes: scientist not being aware of the exact mutations that could possibly occur in humans or the viruses uses in the process of gene therapy, could make the patients that one may say scientist are trying to help, even sicker. "Other commentators have pointed to the difficulty of following up with patients in long-term clinical research. Gene therapy patients would need to be under surveillance for decades to monitor long-term effects of the therapy on future generations (" Subsequently, in using this procedure one must gain informed volunteers. This was reviewed by the Journal of Law, Medicine and Ethics, "The authors discuss the ease with which genetic research is misnamed "therapy", and provide an historical background for this misnomer. While noting that "….the persistent failure to distinguish clearly between research and therapy in medical science" is not limited to genetic protocols, the author suggest that the term "gene transfer research" be used to highlight its experimental nature and deemphasize its therapeutic potential (" Some are troubled that many gene therapy candidates are children too young to understand the ramifications of gene therapy treatment. These children are unable to give voluntary, informed consent, without this step experimentation of this population can not be done. Going off of Kant's, "using people as means to an end"; this is exactly what scientist are using people as now, mean to find a solution to illness, but the repercussions of this action is not fully understood yet. In light of the moral issues mentioned above one can come to the conclusion that even though gene therapy has profound benefit the consequence have proved to be deadly.

After gaining a fully understanding of gene therapy and how it works, the therapeutic nature of this procedure can not be mistake. However, the harms/disadvantages of the procedure outweigh the advantage, because the advantages are uncertain in the way they will help society as a whole. Without knowing for sure the advantages will benefit society one can not ask people to participate is potentially deadly research. According to the article "Human Gene Therapy: Must We Know Where to Stop Before We Start?", "University professor Krimsky criticizes the common distinctions used for gene therapy: somatic v. germ cell, and therapeutic v. enhancement, because the distinctions are too easy to blur, neither should be used ("

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