GENETIC SCREENING AND ETHICS AN OVERVIEW
In 1972 scientists first isolated a DNA segment from a virus and combined it with a piece of bacterial DNA. When this gene was placed into a plasmid and introduced into a bacterium, the introduced gene functioned normally. Thus was born the biotechnology of recombinant DNA, the foundation of genetic engineering.
Genetic engineering is one of the main branches of biotechnology. Cell and tissue culture techniques are a second branch of this technology. These techniques allow researchers to cultivate cells in vitro, transfer embryos from one mother to another, and to fuse nuclei of cells of the same or different species. Mouse hybrid cells are routinely used in many research laboratories.
Diagnostic techniques can be used to identify specific proteins or fragments of DNA. These techniques can be used to detect viruses of animal and plant diseases, to detect harmful substances in the environment, or to match the DNA left at a crime scene to a possible criminal. Diagnostic techniques often utilize DNA probes, RFLP (restriction fragment length polymorphism) analysis, and mono- or polyclonal antibodies.
DNA probes are used to locate and identify genes. Probes utilize the complementary base pairing structure of DNA. The two complementary strands of DNA can denature (separate) and rejoin in exactly the same sequence. A free- floating single DNA strand binds only to the appropriate complementary sequence. Single-stranded DNA fragments can be "labeled" to exhibit color (biotinylated), light (fluorescence), radioactivity, or resistance to antibiotics. When these fragments bind to their complement, the "label " identifies the target DNA sequence. From previous research and " DNA libraries" molecular biologists know that certain probes bind to human DNA near certain genes. When used in combination with RFLP analysis, DNA probes can pinpoint mutations or identify parents.
RFLP analysis is used in conjunction with DNA probing to identify the location of genes. The technique uses restriction enzymes to cut DNA near a suspected gene location into a series of fragments. The fragments are sorted by gel electrophoresis to form a distinctive pattern of DNA fragments. The pattern formed is consistent and unique to each person. The unique patterns occur when one of the two homologous chromosomes inherited from an individual's parents differ because of a mutation at a point where the restriction enzyme cuts the DNA. This creates or destroys a cut site. The mutation adds or subtracts fragments to the pattern of restriction fragments. The difference in the homologous chromosomes is called a polymorphism. The identifiable pattern of fragments is called a RFLP. Researchers examine these RFLPs of families with a known genetic disorder. They hope to find a fragment pattern that is usually inherited with the disorder (all people with the disorder have the same special fragment). This special fragment pattern is called a "genetic marker." DNA probes are made to identify the DNA in the identified fragments.
Antibodies seek out and bind to certain specific proteins. Their use is widespread in home pregnancy tests and in tests to detect AIDS and other infectious diseases (ELISA tests). Monoclonal antibodies can be used to determine compatibility of tissues for organ transplants. The use of antibodies derives from their extreme sensitivity to and specificity for proteins. Each antibody binds to a specific protein even when the protein is present in minute quantities. Specific protein tests can be run inside or outside the body. Monoclonal antibodies are produced by injecting foreign proteins into mouse lymphocytes which have been fused to tumor cells. The fused cells grow rapidly and in culture outside the mouse. The cells produce large quantities of the specific antibody which are purified and will bind with the protein that was originally injected into the mouse.
Biotechnology and Genetics
The diagnostic techniques outlined briefly above are a powerful new tool in all genetics, but most especially in the arena of human genetics. By application of these tools of biotechnology, and other techniques, molecular biologists and geneticists are providing a basis on which to make a genetic diagnosis. Table 1 provides a summary of some of the conditions for which a genetic diagnosis is available, and those conditions for which a gene locus or DNA marker have been identified. Biochemists have located 400 genetic " markers" distributed over all 46 human chromosomes.
The identification of genetic disorders, and the potential for developing a therapy, is a powerful force in genetics and medicine. Table 2 provides information on the prevalence of nine genetic diseases. The numbers of people affected by these disorders alone is significant. The earliest genetic screening techniques examined chromosomes for structural abnormalities. Family histories were obtained and pedigrees were constructed to elucidate the patterns of transmission. The modern use of DNA probing and RFLP analysis now allow detection of genetic conditions caused by mutations of even a single pair of bases. In addition, DNA sequences can be identified that are said to confer "susceptibility" to the condition. In other words, the presence of the gene is associated with increased risk, but occurrence of the condition is not certain. A classic example is neurofibromatosis - the Elephant Man disease. Some people with this gene defect suffer grotesque disfigurement while others in the same family have only a few pigmented spots on their bodies which are never noticed. If you were a genetic tester you would say both people had the gene for neurofibromatosis. Scientists do not understand why the same defect can cause such disparate symptoms.
There is probably no force in a society more powerful than the acquisition of information. The very essence of genetics is, of course, information (genotype and phenotype) on individuals and their families. As modern genetics probes deeper and deeper into the essence of the human genome, the science of genetics will come to possess an information base with power and opportunity for use undreamed of only a few years ago.
Along with this power and opportunity comes responsibility. Genetic intervention techniques such as genetic engineering, human gene therapy, and genetic screening raise many questions. Since these techniques change the flow of information at the level of molecules, the level of individuals, and at the level of societies it is wise to consider to what extent we want to apply these technologies and to reflect on what changes we are seeking. A pertinent question to ask might be whether a technology should be used just because it is available. We need to exercise judgment in our pursuit of these technologies. We also need to understand the options the new genetic technologies will offer so that we can make informed decisions at the individual, local, state, national, and international levels.
Genetic screening for disorders for which a successful therapy exists have been in place for many years. All states of the United States routinely screen newborns for PKU, an inherited disorder for which a carefully monitored diet provides amelioration. But the increasing ability to detect the presence of more and more defective genes has re-energized the ongoing debate about the ethics of diagnosing genetic disorders prenatally, after birth, and in adults.
The majority of researchers and ethicists agree on the importance of diagnosing a disease such as Lesch-Nyhan syndrome, which strikes soon after birth and produces a short, brutally painful life characterized by severe retardation, violence, and self-mutilation. Few ethicists see a problem in prenatal screening for such conditions as long as abortion is a legally obtainable option. But the issues are different in diagnosing a disorder such as familial Alzheimer's disease which produces no symptoms until it s trikes as early as age 45, or in the case of polycystic kidney disease which produces no symptoms until adulthood and even then progresses slowly. This ability to detect presymptomatic genetic conditions, susceptibility to genetic diseases such as hyperchlosterol or alcoholism, or the ability to identify carriers of recessively inherited conditions such as cystic fibrosis, poses new challenges to the ethical frameworks that had previously been established to deal with controversial detection programs. The sickle cell anemia detection program of the 1970's provided a widely accepted ethical model that included voluntary participation in screening programs. The 1970's guidelines established that screening was appropriate if the genetic disorder was serious, the test was accurate, and a therapy or intervention was available. The cost of the screening technique was to be in proportion to the benefits to be derived from the program. No unreasonable burden was to fall on those falsely identified as ill or on those individuals who were screened but were found not to be affected. These criteria seem inadequate given the expanded methods and the range of present day molecular genetics.
One of the problems posed by recent developments in molecular genetics is the actual definition of what constitutes a "disease." There is precedent for defining deviations from the statistical norm, such as high blood pressure or obesity, as "disease." However it is appropriate to ask if a late onset condition such as polycystic kidney disease is really a "disease" at all. If a woman inherits a mutation of the p53 gene and has an increased susceptibility to cancers of the epithelial cells, yet lives cancer-free for many years, does she have a "disease?" When the full human genome -- the collective name for all human genes -- is mapped, we risk greatly expanding the numbers of people who do not fit our definitions of normal, able, and healthy.
The significance of the debate about what constitutes a disease is underscored by the two broad questions which underlay the current debate: Who decides whether or not testing is done; and what happens to that information? Clearly genetic screening is going to be done. The question is how are we going to use it and what social limit will we put on it? There is an apparent discrepancy between the reality of genetic variability and the democratic ideal that all citizens are "created equal." Possible outcomes of genetic screening experts see are:
Other troubling questions loom on the horizon:
As we consider these questions it would be wise to remember that less than half of all disease and disability is thought to be caused by genetic factors. Each human is also thought to carry about five recessive genes for lethal disorders. We will probably discover that all of us carry a large number of genes that predispose us to various conditions. We all share the human condition. We will, all of us, become ill at various times. We all will, with certainty, grow old and die. Perhaps this fact alone will temper our judgment about who will be screened for genetic disease for we might find ourselves weighed in the balance.
I. Genetic diagnosis is currently available for the following:
II. Inherited conditions in which DNA markers have been found:
III. Inherited disorders in which disease gene locus has been identified:
[Adapted from Harry Ostrer and J. Feilding Hejtmancik, " Prenatal diagnosis and carrier detection of genetic diseases by analysis of deoxyribosenucleic acid," Journal of Pediatrics 112(5):679-687.]
PREVALENCE OF SOME GENETIC DISEASES
Estimates of the number of Americans having diseases with a genetic cause or an important genetic component
Source: Office of Technology Assessment