The pace of discovering new molecular genetic information has been astonishing in recent years – in no small measure due to the Human Genome Project and the competing efforts of private companies such as Celera Genomics. It has been estimated that the total amount of genetic information now increases by a magnitude every five years. Indeed, Victor McKusick's magisterial Mendelian Inheritance in Man – a comprehensive compendium of information about human genes, gene maps, genetic diseases, statistics, pictures, and other genetic information with references linked to MEDLINE – is now maintained as a continuously updated and publicly-accessible database at http://www3.ncbi.nlm.nih.gov/Omim.
Processing this avalanche of data has stimulated the marriage of information technology and genetics to spawn the new field of genomics.
This new genetic information will permit the development of widespread genetic testing and gene therapy for a huge number of genetic diseases. Multiplex testing will become possible in which, at a single setting, a wide variety of genetic diseases can be screened simultaneously. And the identification and testing for single nucleotide polymorphisms will revolutionize pharmaceutical development by identifying in advance patients who respond to particular medications.
CONSENSUS ON ETHICAL GUIDELINESS
Each of these marvelous scientific advances raises ethical issues that deserve thoughtful consideration. Presently, the Human Genome Project Working Group on Ethical, Legal, and Social Issues as well as numerous university-based groups are working to address these questions and develop guidelines for the optimal use of genetic information to benefit individuals and society.
A consensus has emerged on the fundamental ethical and related issues, following statements from the Institute of Medicine and the President's Commission for the Study of Ethical Issues in Medicine and Biomedical and Behavioral Research. These principles deserve our attention and response as neurologists.
UNDERSTAND GENETIC TESTING
First, it is a physician's duty to be knowledgeable about genetic testing. This knowledge base includes understanding the types and availability of genetic testing for diagnosis, screening, preventive testing, and predictive testing of genetic disease. Physicians further need to understand the meaning of a positive or negative test and its implication for their patient. Unfortunately, several studies have shown widespread misunderstanding among physicians about the meaning of genetic tests they order. Consider, for example, the use of APOE e4 allele testing in Alzheimer disease. The availability of this test was broadly reported in the popular press and many patients requested it. Some neurologists complied with their patient's requests for the test, despite the fact that they lacked a clear understanding of the medical and scientific issues involved and, for that matter, the meaning of the results.
Dr. Bernat is Professor of Medicine (Neurology) at Dartmouth Medical School.
Three recent independent analyses concluded that, aside from the research context, DNA predictive testing for Alzheimer disease is unwarranted in clinical practice, except in the rare instance of a patient from a family with documented early-onset Alzheimer of autosomal dominant inheritance.
INFORMED CONSENT IS CRITICAL
Informed consent is the indispensable prerequisite for genetic testing. Genetic testing, screening, and predictive testing all require the free and informed consent of the patient. Patients should understand the implications of their test result and should have the opportunity to receive psychological and genetic counseling as part of the testing program.
Tests should not be ordered by third parties and patients should not be coerced into testing without their free informed consent. Consent for testing in children can be provided by their parents, but children should not be subjected to predictive testing for diseases of adult onset, such as Huntington disease. Such predictive testing should be postponed until the patient is 18 years of age and can consent independently.
PROTECT PATIENT CONFIDENTIALITY
The misuse of genetic information represents a serious ethical problem. Most instances of misuse arise from violations of the confidentiality and privacy of genetic information. Physicians should not share patients' genetic information with third parties or release it to agencies without the patient's consent, unless required by law. Violations of confidentiality can lead to patients losing their jobs or insurance. Many hospitals have devised information protection systems to enhance the confidentiality of genetic information in much the same way as they have for protecting information on patients' HIV seropositivity status.
Since 1991, over half of US states have enacted laws restricting or prohibiting health insurers from using patients' genetic information in pricing, issuing, or structuring health insurance. The federal Health Insurance Portability and Accountability Act of 1996 prohibits group health insurers from applying the “pre-existing condition” exclusion to genetic tests in the absence of symptoms or signs of disease. The Americans with Disabilities Act of 1990 further protects the confidentiality and equal opportunity of patients who are carriers of genetic disease or who are destined to develop genetic disease.
RISKS AND USES FOR GENE THERAPY
Gene therapy raises another group of challenging ethical issues. Once the consent, safety, and scientific issues are resolved, there is probably nothing ethically unique about conducting somatic cell gene therapy or fetal gene therapy to correct genetic diseases.
A controversy presently swirls around gene enhancement therapy – where gene therapy is applied to improving the appearance or enhancing the already normal functioning of a person. Although some have plausibly argued that the risks of gene therapy for enhancement may not exceed the risks of alternative pharmacotherapy, most people concur that societal priorities should assign public payment preference to using gene therapy to correct disease.
The question of germ-line gene therapy is another matter. In germ-line gene therapy, the therapeutically-induced genetic alteration affects all subsequent generations. How can we assure safety when the impact several generations thereafter remains unknown? And how can the valid consent we obtain now from the index patient ever adequately apply to alterations that affect people in future generations?
Because of these insoluble problems, last April, the American Association for the Advancement of Science issued a report calling for a total moratorium on all germ-line gene therapy. Following a two-year series of consultations with leaders in the fields of gene therapy, ethics, sociology, and theology, the authors of the report found a strong consensus for the hard-line position of banning all further research in germ-line gene therapy. In their proposed moratorium, the AAAS also included related lines of research that might plausibly but accidentally damage germ-line DNA producing alterations affecting future generations.
WHAT NEUROLOGISTS CAN DO
What do these considerations mean to practicing neurologists? First, neurologists need to educate themselves about the scientific basis for genetic tests and the meaning of results they contemplate ordering. Second, neurologists should follow accepted guidelines on the use of genetic tests, such as those developed for APOE e4 allele testing in Alzheimer disease. Third, neurologists can encourage the enactment of public laws that protect the confidentiality and privacy of patients to protect their patients from experiencing unjustified discrimination in the workplace or in obtaining insurance. Finally, all physicians should try to adopt an attitude of humility and attempt to exercise wisdom in our use of new technologies by thoughtfully considering the harms they might create as well as their possible benefits.
