Dr. Roli Mathur*
Senior Research Officer at the Division of Basic Medical Sciences, Indian Council of Medical Research,
|The completion of the first draft of the Human Genome Project has created both exciting opportunities and tremendous challenges for researchers. In translating discoveries for disease prevention and health promotion, it is also necessary to ensure appropriate use of genetic information and technologies keeping in view the general principles of ethics. Genetics has entered the practice of neurology and the last decade witnessed the discovery of the genetic basis of many diseases that primarily affect the nervous system. In areas such as neuromuscular and movement disorders, genetic testing has become a routine part of diagnostic testing.
In areas such as neuromuscular and movement disorders, genetic testing has become a routine part of diagnostic testing.
There are complex issues such as the appropriateness of genetic testing in specific clinical situations as well as privacy issues that neurologists will confront more and more in the future. It is thus important to review the basic principles of genetic testing, its application to neurology, and some limitations and ethical issues confronting the field.
Advances in molecular genetics have led to new diagnostic tools. As an example there are more than 15 known neurogenetic disorders involving trinucleotide repeat expansion. Expanded repeats range from small expansions of 20-100 copies to larger expansions of up to several thousand units. These dynamic expansions result in variability in age of onset, degree of severity and clinical presentation. Individuals carrying alleles in the intermediate range, known as permutation alleles, are often asymptomatic, but can potentially transmit a further expanded allele to his/her offspring. For autosomal dominant adult-onset disorders, carriers are asymptomatic prior to disease onset. With current molecular tools, it is now possible to determine the presence and number of expanded repeats for accurate diagnosis, presymptomatic testing and carrier status screening for many conditions. The abnormal genes and their protein products as sociated with neurodegenerative diseases such as Huntington's chorea have been identified and the genetic risk factors for Alzheimer's disease are known. However, for neither of these conditions has the new genetic knowledge brought about any effective treatment or prevention. Progress in the genetics of neurogenetic disorders and the availability of clinical tests for practicing physicians has increased the need for a better understanding of multifaceted issues which may be quite complex and raise many ethical concerns. The other concern is that in Genetics the distinction between research and service is often not very clear and Physician-Researchers role is utmost important for safeguarding interests of their patients/research participants.
The other concern is that in Genetics, the distinction between research and service is often not very clear and Physician-Researchers role is utmost important for safeguarding interests of their patients/research participants.
Research studies using human subjects have long played an essential and irreplaceable role in advancing biomedical and behavioral science, thus enhancing our ability to treat illness and better understand human behavior and functions. In recent decades, however, researchers have become increasingly sensitive to the ethical issues associated with such research studies, especially as they concern the rights and welfare of subjects. As a result, ethical guidelines been established to ensure that such studies meet appropriate ethical standards for the protection of human subjects. The two most fundamental measures developed to meet this goal are an independent review of protocols by an institutional ethics committee (IEC), and the informed consent of human subjects. The investigator is the key player in our research system with respect to the protection of human subjects.
|Principles of Bioethics - Autonomy, Beneficence, Non-maleficence & Justice|
|The Ethical Principles in medicine and research, autonomy, beneficence, non-maleficence and justice enumerated in the ethical guidelines of Indian Council of Medical Research, 2000 also apply to genetic research including neurogenetics. In fact the main concerns in Genetic Research extend beyond general ethical concerns. Major Ethical, Legal and Social Issues need to be continuously debated and require attention to understand reasons and ways to protect autonomy, privacy, confidentiality, preventing stigmatization and discrimination of subjects. On one hand genetic information could be extremely useful in preventing, as well as in early diagnosis and treatment of genetic disorders, while on the other, it could also be a threat to human rights and fundamental freedoms including human dignity and autonomy.
- Informed Consent - If human beings must become research subjects their respectful treatment begins with soundness in research design and their voluntary agreement to participate in research. An ethically justifiable clinical research should take into account the wide variations in the conditions that may affect the decision making capacity of potential human subjects. Genetic conditions require detailed explanation to allay fear and misunderstanding. Non-directive counseling by an appropriately trained person about benefits and utility of the research, its limitations as well as alternative procedures is integral to genetic research because results of genetic tests often have complex implications, including those for the family and the community.
- Risk Benefit Assessments - It has long been recognized, for example, that unless the researcher is a competent investigator and the research design is sound, it is inappropriate to attempt to recruit research subjects, regardless of the level of risk. Even with the best research designs, however, research protocols can rarely eliminate all risks. In neurogenetic conditions the risks may often not only be physical but also psychosocial. The direct or indirect benefits as well as risks must be carefully weighed and considered by the ethics committee as well as researchers to put appropriate safeguards into place for better protection.
In neurogenetic conditions the risks may often not only be physical but also psychosocial.
- Justice Issues - Any specific population group should not be exploited, and it is an ethical responsibility of the research community to ensure that any population should never shoulder all the risks and burdens of a scientific project when the benefits are expected to flow primarily to another population group. Population genetic studies can be sometimes stigmatizing and selection of subjects/population groups should be fair and benefits of such research should also come back to the contributing community.
|Privacy and Confidentiality |
|Private and identifiable information of research participants should be handled with care and never disclosed to any third party. It is important to realize that neurogenetic information is generally sensitive in nature and disclosure may have long term or far reaching consequences. Genetic information not only reflects upon an individual but also on the relatives and family. There are issues concerning genetic diagnosis and who and under what conditions, should have access to this information. Many individuals (relatives) and agencies (employers, health insurers) have claims on the information. What balance should be struck between their claims and the individual's right to privacy? There are concerns regarding the way private insurers may deal with the issue of genetics and insurance. All of these issues need to be debated and need careful handling. There are also issues related to protection of information abo ut secondary subjects as genetic diseases run in family and often concerns not only an individual but several family members. At the time of pedigree charting appropriate consent should be obtained from the secondary subjects if identifying information is being collected about them.
At the time of pedigree charting, appropriate consent should be obtained from the secondary subjects if identifying information is being collected about them.
|In neurogenetic research, when disease processes themselves are under study, the absence of animal models for most neurologic syndromes means that research on both the underlying dynamics of disease and promising treatments must, at some stage, involve human subjects. This may also involve subjects whose decision making capacity may be impaired leading to the central problem of designing appropriate protections for persons with any kind of ailments who participate in such research protocols, while providing the opportunity to obtain the potential for benefit that may arise from their participation and, to some more limited extent, the potential benefit for other persons with the same disorder. Research on subjects unable to consent for themselves or who have diminished autonomy like cognitively impaired individuals, children etc it becomes the ethical responsibility to provide adequate safeguards for optimal protection in re search. It is also best to avoid recruiting vulnerable populations in the study unless it is for a direct benefit or targets a disease or condition found only in the vulnerable population group. |
|Multifactorial conditions |
|Most researchers readily accept the existence of a complex interplay between genes and environment for several neurogenetic conditions. A large number of common disorders are now emerging as complex multifactorial disorders where both genes and environment are considered to play role in causation of the disease. There is a lot of work to be done so that molecular genetics tools are used to the benefit to patients. However it is necessary for investigators to be aware of recent progress in the genetics and of the clinical and ethical considerations regarding disease prediction for multifactorial conditions as there are several factors into play. Unlike single gene disorders, the disease expression, age of onset, degree of severity of the disease etc may vary depending on multiple contributing factors. Therefore any diagnosis in this regard must be done with utmost care after ethical justification.
|Pre-symptomatic Diagnosis |
|With newer genetic technologies, it has also become possible to screen and diagnose presymptomatic individuals for susceptibilities for late onset disease conditions. However premature introduction of genetic testing for susceptibility (risk) analysis in asymptomatic individuals can have possible adverse consequences. An example is the Apolipoprotein E (APOE) polymorphisms which are found to be associated with variable risk and age of onset distributions for the common form of Alzheimer disease. Disease prediction may be possible however preventive therapies are not yet available.
However, premature introduction of genetic testing for susceptibility (risk) analysis in asymptomatic individuals can have possible adverse consequences.
This can have far reaching social, ethical, and legal problems. Huntington chorea is another classical example as it is an autosomal dominant disorder with high penetrance, but clinical manifestation is usually after 40 years of age. Sometimes individuals at risk (with positive family history in one of the parents) are interested to know about their definitive status. However, since no intervention is available to prevent, delay or ameliorate the disorder, the test should be offered only after intensive pre-test counseling as a positive test result could lead to serious psychological problems. Testing susceptibility genes becomes unethical as it has only a limited diagnostic value at present and generally not recommended because in most cases individual risk cannot be quantified and no therapeutic interventions can be offered.
Testing susceptibility genes becomes unethical as it has only a limited diagnostic value at present and generally not recommended because in most cases individual risk cannot be quantified and no therapeutic interventions can be offered.
|Prenatal & Preimplantation testing |
|Prevention of birth defects and genetic diseases is aimed at averting deterioration, complications, disability and dependency of the patient and the family. The aim is to maximize the chances that individuals at increased risk of affected offspring have children free of the disorder. Information about the purposes, benefits and limitations of prenatal testing methods or tests should be discussed so that voluntary decisions can be taken. Most couples at increased genetic risk of a serious neurogenetic disorder or birth defect would favor prenatal diagnosis to avoid the birth of an affected infant however there are various considerations like technical, financial, cultural, legal and religious factors which may influence decision making. It is also possible to screen embryos for many known genetic diseases. Given the choice through in vitro fertilization and the ability to test for behavioral traits, many parents fe el that they have a right to select the child that best suits them, even selecting for non-disease traits intelligence, cosmetic reasons like better looks or athletic physique. Use of genomic information should be judicious and requires due care. Preimplantation diagnosis and selection of embryo raises a large number of ethical controversies.
|Newborn screening (NBS) is now possible for up to 50 specific metabolic disorders for early detection and intervention in the population. In India with a birth rate of 25 millions every year this holds the promise of improving the lives of thousands of affected children. However there are economic and social forces posing significant ethical and clinical challenges to NBS. There is a need to identify the common diseases of the region for which an early intervention, treatment or management is possible and can reduce the disease severity. Appropriate counseling services should be made available for newborns found to be at risk/affected to make the program feasible, cost effective and ethical. |
|Storage of Samples for future Research Use|
|When samples used for genetic testing have to be stored for future academic/research purposes, besides informed consent, it is advisable to delink personal identifying information of the individual from the sample and genetic data with the help of a code held securely, unless it is necessary to retain the identity for research purposes. For a lot of basic research the samples may be anonymised and used after approval from the Institutional Ethics Committees.
When samples used for genetic testing have to be stored for future academic/research purposes, besides informed consent, it is advisable to delink personal identifying information of the individual from the sample and genetic data with the help of a code held securely.
Anonymisation or delinking will help in ensuring privacy and confidentiality of genetic data. However delinking of identified data from the sample does not exclude the necessity to obtain informed consent. Every use of stored biological material requires that informed consent be obtained specifically for each research.
Anonymisation or delinking will help in ensuring privacy and confidentiality of genetic data.
|Ethical, legal, and social issues (ELSI) in Genetics|
|Genetic Disorders have always been considered rare and often a taboo in our population. There is very little awareness and knowledge not only in public but also among medical professionals. Genetic Services are uncommon and considered expensive and unreachable for common man. The tradition for respecting individual freedom and autonomy is not well established. Because of illiteracy and rural background, many patients leave medical decisions to their doctors but the importance of voluntary informed consent is not appreciated by patients or doctors and considered merely a formality of signing on a sheet of paper. There is rampant poverty and illiteracy. All this requires extra effort, both on part of treating doctors and researchers, to maintain high ethical standards and to obtain free, informed consent after making independent choices in a research setting. Various questions are raised like the possibility of obtaining fully informed consent from large populations, possibility of providing only limited information about the genetic information being sought, measures for protecting privacy and maintaining confidentiality in public health registries and databases, preventing group stigmatization and discrimination. None of these issues have easy solutions, but they raise important challenges for the public health community. |
|We are at the dawn of the neurotechnological age. In the last decade, huge amounts of data have been collected in the fields of neuroimaging, psychopharmacology and genomics. Genetics is at the same time exciting and perilous, and now is the time to begin serious discussion of the implications of these emerging technologies for society. As these technologies become more sophisticated, they will have far-reaching socio-economic, legal and ethical implications. The elucidation by neuroscientists of the biological bases of phenomena such as cognition and emotion, once believed to be outside the realm of science, will raise philosophical questions about the nature of the 'self' and what it means to be human, and the reduction of human behavior to neurobiological mechanisms will make us question ideas such as human freedom and responsibility. Ultimately, the decision whether or not to embrace these new technologies must be taken in light of the various ethical considerations. |
- Ethical Guidelines for Biomedical Research in Human Subjects (2000). ICMR, New Delhi.
- Research involving persons with Mental Disorders that may affect decision making capacity. Vol. I report & recommendations of the NBAC, 1998.
- Ethical Policies on the Human Genome, Genetic Research and Services (2002). DBT, Govt. of India.
- Nuffield Council on Bioethics. Working Party on Genetic Screening : ethical issues. (www.nuffieldbioethics.org/geneticscreening).
- Harper, P.S., Lim C., Craufard, D. Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium. J. Med Genet 2000;37:567-71.
- Useful online resources on ELSI of human genomics, WHO (2004). (http://www.who.int/genomics/elsi/resources)
- Van Hoyweghen I, Horstman K, Schepers R. 'Genetics is not the issue' : insurers on genetics and life insurance. New Genet Soc. 2005 Apr;24(1):79-98.
- Paulson HL, Neurol Clin. Diagnostic testing in neurogenetics. Principles, limitations, and ethical considerations 2002 Aug;20 (3).
|How to Cite URL :|
|Mathur R D.. Available From : http://www.pediatriconcall.com/fordoctor/ Conference_abstracts/report.aspx?reportid=388|