The sound of clapping on a back, a brutal cough, spitting. These were the sounds of Camilla’s room. As a teenager, I had difficulty understanding the meaning of cystic fibrosis in Camilla’s life. It is only talking to her at this junction in our life, our senior year of college, that I have realized the absolute difference in our two lives. I look forward to a long career and hopes of building a family with two, maybe three children. Camilla cannot afford to have such brilliant aspirations. As her cystic fibrosis grows steadily worse, she faces early death and knowledge that having children poses a great risk they will also have CF.
Fortunately for Camilla and others with CF, rapid advances have been made in cystic fibrosis treatment and prevention. Until recently, the twelve million Americans who are carriers of the cystic fibrosis gene would never know it unless two of them had a child with CF. During the past ten years, however, the gene that causes cystic fibrosis has been mapped and testing for the faulty gene is widely available. However, cystic fibrosis has unleashed a tidal wave of controversy involving issues such as genetic screening, privacy issues, and gene therapy. The response of American society and the government to these issues will be an important factor in the formation of national policy regarding genetic testing and gene therapy for years.
Cystic fibrosis is caused by a mutation in the cystic fibrosis transmembrane conductance regulator or CFTR gene. The protein encoded by the CFTR gene in its normal form regulates the level of water and salt in cells. Specifically, CFTR codes for a tunnel-like protein through which cells secrete salty ions (1). A mutation in the CFTR gene causes inefficient ion transport. As a result, thick mucus forms and lines the lungs and digestive track. This mucus can cause numerous problems throughout the body.
The symptoms of cystic fibrosis are actually the result of over six hundred different CF mutations and possible interactions with other mutations and the environment. Mutations disrupt normal gene function in five different ways: no protein synthesis, a block in processing, block in regulation, altered conductance, and reduced synthesis (2). The most common mutation, the (delta) F508 mutation, results in retention of the protein in the endoplasmic reticulum and degradation (2). Mutations may also affect other ion transport proteins, resulting in a more severe phenotype (2). As a result of the many different mutations that contribute to the cystic fibrosis phenotype, the severity of health problems cannot be predicted by the genotype of an individual.
Cystic fibrosis patients suffer a number of significant health difficulties eventually leading to early death. In the cells of their lungs and digestive track, thick mucus forms due to ineffective ion transport (3). This mucus obstructs and degrades the lungs resulting in declining pulmonary function over the course of a patient’s lifetime. As bacteria invade their mucus-filled lungs, CF patients often experience difficulty breathing and frequent respiratory infections (4). In the pancreas, mucus blocks the enzyme-producing pancreas and results in inefficient digestion (3). As a result, most CF patients suffer malnutrition, poor growth, and abdominal pain (4). The life expectancy of those with cystic fibrosis is 29 and the most common cause of death is lung disease.
During the past decade, scientists have researched the possibility of gene therapy for this disorder. The idea behind gene therapy of cystic fibrosis is that using a vector, it would be possible to insert a normal copy of the CFTR gene into the airway. Research has focused on using three different vectors: adenoviruses, adeno-associated viruses, and liposomes (2). In 1992, Ronald Crystal at the National Lung, Heart, and Blood Institute successfully used a disabled adenovirus vector to insert a healthy human gene into rodent lung sells (5). Unfortunately, when this treatment was utilized on the first human patient, the original viral DNA retained in the vector provoked an immune system response (6). The possibility of gene therapy for cystic fibrosis could mean ending the suffering of CF patients through pulmonary dysfunction.
Developments in mapping the human genome and gene therapy have raised significant ethical debates. To many, the ability to manipulate the human genome is a fearful idea. Our genetic makeup is the basis of all our bodily functions – do humans have the right to ‘play God’ in any way? Opponents of gene therapy worry about whether humans will know when to stop with these techniques. While many have argued against genetic advances, the equally impassioned response recognizes the horrible suffering of so many from genetic disorders such as cystic fibrosis (7). Why should we worry about these ‘ethical’ questions when we may soon be able to end the pain of certain genetic disorders? We use many types of treatments in today’s medicine. Gene therapy is one more treatment, a treatment that could silence Camilla’s terrible cough.
Scientific research on cystic fibrosis has moved at an extremely fast pace during the past decade. In 1989, the CFTR gene was mapped to chromosome 7 (2). Since then, there have been significant advancements in the ability of the test to detect mutations. Currently, the test is used to identify six different common mutations for cystic fibrosis. Hybridized pieces of DNA, called allele specific oligonucleotide probes, are used to bind to a test strip with DNA samples from an individual (8) . Colorimetic analysis is used to reveal that the probes hybridized to one of two dots for each location. The right dot, indicates a CF mutation while the left dot indicates the person is normal for the CF gene at that location. Carriers show weak dots on both sides of the panel (8). These developments in genetic screening have enabled the medical profession to test both patients with the clinical symptoms of CF and carriers for the cystic fibrosis gene.
As one of the first genes to be mapped for a serious disorder, cystic fibrosis has attracted national attention in the debate concerning genetic screening. Three types of genetic testing for CF are now widely available: carrier identification, prenatal testing, and neonatal screening. The National Institutes of Health has recommended that genetic testing for mutations causing cystic fibrosis be offered to all pregnant couples, couples planning a pregnancy, partners of people with CF, and those with a family history of CF. NIH does not advocate newborn screening and universal carrier screening because they do not believe these tests have any medical benefits (10).
One of the arguments against genetic testing for cystic fibrosis is the questionable accuracy of the test. Although the test has improved since the CFTR gene was first located, it continues to provide erroneous information on occasion. Because of the many mutations involved, genetic testing misses about 10% of cystic fibrosis cases, particularly those with pancreatic dysfunction (11). Consequently, a negative test result does not rule out the possibility of the disease. Parents may be relieved to get a negative result only to be devastated later to find that their child actually has CF. Even positive results do not provide a great deal of accurate information as they cannot predict the severity of the disease. On occasion, genetic testing has identified someone as having cystic fibrosis who had no idea that they were ill (12). Such diagnoses and the confusion created by confusing test results can only cause undue stress and unhappiness. Only with improved accuracy in testing will some of these fears and problems become solved.
Privacy issues have been a significant concern since the first genetic tests were developed. The denial of insurance coverage on the basis of genetic information is a scary phenomenon. If two carriers for cystic fibrosis decide to have a child, will they still be able to obtain insurance coverage? Carrier status itself has already been used to justify the rejection of insurance. In a survey conducted by the Office of Technology Assessment, twenty-four percent of medical directors at insurance companies stated that "carrier risk for genetic disease" was "very important" or "important" to un-insurability (8). Indirectly, insurability can also affect employment. Forty-two percent of employers surveyed said that the insurability of a healthy job applicant could reduce the likelihood they would be hired (8). Insuring the privacy of test results is essential to prevent discrimination against CF carriers by insurance companies and employers.
One of the most important problems in any type of genetic screening is education and the ability to interpret test results. In the early 1990s, the Human Genome Research’s ‘Ethical, Legal, and Social Implications’ (ELSI) conducted a study regarding CF testing that demonstrating that many of those tested had difficulty interpreting the results. According to ELSI, only 44% of those who tested negative understood that, due to the 90% accuracy of the test, they could still give birth to a child with CF (13). Because many individuals don’t understand genetic principles, they may have difficulty grasping what their results mean. Low numeracy can also affect the ability of people to understand the meaning of the results of genetic testing (14). Because it is essential for individuals to accurately understand the results of the CF test, it is necessary to provide ample education and counseling. Insurance companies advocate lowering counseling services because they increase the cost of testing (15). Because the inaccurate interpretation of test results could be psychologically devastating, it is essential to establish rules regarding genetic counseling in order to insure that test information is received accurately.
The screening of couples for carrier status is an ethical dilemma. Carrier screening is the screening method of choice for insurance companies and health-care providers that emphasize the importance of using the most cost-effective testing method. Because carrier testing provides information before pregnancy, prevention can be achieved without significant medical treatment (16). It is also an important screening method for those who have a moral dilemma concerning abortion but do not want to have a child with CF. However, some have questioned the nature of the information sought in carrier screening. According to authors Stone and Stewart, "to inform the reproductive choices of individuals and couples at risk…represents a paradigm shift in the philosophy of screening in that no preventive principle is involved." Regardless of the couple’s decision once they have the results of the test, carrier status is useful information. Some fear those involved in genetic testing will begin to utilize it without regard to ethical principles and currently accepted screening practices (17). Although carrier screening could go too far, it might allow the possibility to virtually eliminate the cystic fibrosis gene through high-risk carrier screening and careful reproductive decision-making.
The advances in genetic screening for cystic fibrosis have raised a number of important ethical issues. In the scope of this essay, it is only possible to cover a few of the important ethical questions associated with genetic testing. However, it is clear that inaccurate test results, denial of insurance coverage, and misinterpretation of results can cause significant problems for people. But with proper education and regulations, these difficulties can be overcome. In the development of genetic screening as a medical tool, it is extremely important to establish rules to protect privacy and educate the public about genetic disorders. With proper education and regulation, genetic screening gives us the power to make proper reproductive decisions and work towards the elimination of a horrible genetic disease. For Camilla and others with CF, genetic screening provides the possibility of having children with someone who is not a CF carrier. Genetic screening, if used with care, has the possibility of improving the lives of cystic fibrosis patients, their families, and anyone concerned with transmitting a deadly disease to their child.
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(2) Rosenstein, Baryl and Zeitlin, Pamela, "Cystic Fibrosis", The Lancet 351: 277-282 (1998).
(3) Norvell, Candyce, "The Facts on Cystic Fibrosis", Current Health 2 21: 22 (1995).
(4) National Heart, Lung, and Blood Institute, "Facts about Cystic Fibrosis," NIH Publication No. 95-3650 (1995).
(5) "CF Gene Therapy on Horizon", Science News 141: 23 (1992).
(6) Carey, John, "The $600 Million Horse Race", Business Week August 23: 68 (1993).
(7) Postrel, Virginia. "Fatalist Attraction", Reason 29: 4-6 (1997).
(8) Congress of the U.S., Office of Technology Assessment, "Cystic Fibrosis and DNA Tests: Implications of Carrier Screening" (1992).
(9) Featherstone, Carol. "Old Hopes and New Horizons for Treating Cystic Fibrosis", the Lancet 347: 1544 (1996).
(10) Human Genome News, "CF Genetic-Testing Panel Emphasizes Education", http://www.ornl.gov/TechResources/Human_Genome/publicat/hgn/v9n1/13cf.html
(11) Kmietowicz, Zosia, "Call for Routine Cystic Fibrosis Screening", British Medical Journal 315: 899-904 (1997).
(12) Human genome News, "What Can the New Gene Tests Tell Us?" World Wide Web. http://www.ornl.gov/TechResources/Human_Genome/publicat/judges/judge.html
(13) Marshall, Eliot. "ELSI’s Cystic Fibrosis Experiment", Science 274: 489 (1996).
(14) Brad Arrick, Bio 4 Class Lecture, 3/4/99.
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(17) Stone, DH and Stewart, S., "Screening and the New Genetics: A Public Health Perspective on the Ethical Debate", J Public Health Med 18: 3-5 (1996).