Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Director & Professor, Center for Human Genetics, Boston University, USA.
Genetic disorders are common and given the fact that we each have 50,000-100,000 genes in each of our cells, it is surprising that even more illness than occurs is directly due to genetic mutation. There is a considerable recognized "burden" of disease resulting from genetic abnormalities, either chromosomal, single gene or polygenic in origin (1)(2). We all carry a number of harmful genes and over 6,000 single gene disorders or traits have been catalogued (4). Between 1 in 8 and 1 in 10 sperm or ova have chromosomal abnormalities. About 50% of ova of women with infertility have been found to have chromosomal abnormality. Moreover, about 1 in 3 conceptions have a chromosome defect. Major congenital defects, genetic disorders, or mental retardation occur on average in 3-4% of all births. The prevalence of these disorders rises to 7-8% by 7 years of age, and at least 1 in 12 individuals have some type of genetic disorder. Major congenital defects, genetic disorders and mental retardation account for 25-30% of admissions to Children's hospitals in North America, Canada, and the United Kingdom. Anatomical major defects alone occur with a birth frequency of about 2%. A chromosome defect is found in 50% of first trimester miscarried embryos or fetuses. Stillborn infants or those succumbing in the first 24 hours after birth have a chromosomal abnormality frequency of 6-11%.
Research and Reality in a Global Perspective
I would first like to make six distinct points. First, infectious diseases still occupy the central attention of all developing countries, while the opposite is now true in so-called developed countries. However, the new genetics has an important place in developing countries, best exemplified by the introduction of testing for the hemoglobinpathies of sickle cell disease and thalassemia. Very important in-roads into decreasing morbidity and mortality have been made, without great expense.
A second point relates to the contribution of genetic disorders to infant morbidity and mortality in developed countries. More and more we recognise contributions from a genetic source to decreasing the frequency of morbidity and mortality and the associated costs.
The third point is that the world has become much smaller, by virture of the media exposure, through television and film. In consequence, people in the far reaches of China or Russia or elsewhere now get to hear about genetic engineering. very distant from their lives daily routine. They are beginning to ponder these questions when much more fundamental matters of health care are yet to be delivered to them. Nevertheless, they share a fundamental, universal emotion. Certainly the mothers of Russia, Japan, China and elsewhere, share the common anxiety and hope to have a healthy child. It turns out, in countries like the United States, this is no longer simply a wish or dream but an expectation. This has translated more recently into the public turning to their lawyers for assistance in recognising their dreams and aspirations about having a healthy or normal child. These lawyers in turn have assailed physicians for failing to keep up to date, or failing to practice medicine at an accepted standard of care, and against who they have brought major legal claims for negligence in these areas. As a consequence there has been a large explosion of litigation in medical genetics in the United States. It is a truism that what happens in the United States inevitably, and perhaps sadly, will slowly spread across the world. It is not difficult to predict that lawyers will begin to interfere with medical practice in other places. It is also important to recognise that lawyers have done for patients more than they are given their due. In other words, without the attention of plaintiff attorneys many patients would be, and would continue to be, deprived of the new technologies that they or their families and children can benefit. So despite the many derisive jokes and other statements about lawyers in the United States, they unfortunately perform a function that upsets physicians incredibly much. Nevertheless, their involvement has changed standards of hospital and medical practice in a permanent way, and has enshrined the rights of all patients for their autonomy and for them to benefit from technologies that even their physicians refuse to keep up with.
Fourth, there have been repeated references to education in this seminar. Education in the context of genetics stretches in a global fashion over many areas. It is true to say that all over the world medical students are poorly educated in medical genetics. We can talk about bioethics for the next year continuously, but if we do nothing about the education of future physicians about bioethics and medical genetics we may as well be talking into a vacuum. There are few departments of human genetics in medical schools the world over. In the United States less than 20% of medical schools have a fully fledged department of medical genetics in a medical school. Every effort should be made to remedy this problem the world over.
Public education the world over in genetics is appalling. I felt perhaps cynically, the need to educate the public directly, rather than waiting to educate a generation of physicians who then hopefully would benefit the patients. I began to write books for the lay public. The first book, Know Your Genes, was published in 9 languages, including Japanese. Subsequently the book is in its third edition under a different title, Heredity and Your Family's Health (1). In fact when I first published the book in 1977, we provided a high school educational program called the "Gene Scene". My colleagues and I spoke to 12,000 high school students, in groups of 600-800 at a time, and I cannot tell you how very compelling the subject was to 11th and 12th grade high school students at the end of their school careers.
Continuing on this theme of educational need, we find that legislators all over the world require education in medical genetics. In the state of Georgia in the 1960s there was a remarkable effort in the legislature to enact a law providing immunisation against sickle cell disease! That gives you some idea of the requirements we have to educate people who make laws that are nonsensical.
Fifth, only now in the United States has medical genetics been recognised as a formal medical speciality by the American Medical Association, which has for the first time this last year incorporated medical genetics into the formal list of specialities recognised in the field of medicine. This is despite the fact that Board Certification in Medical Genetics through the American Board of Medical Genetics has been possible for more than a decade. Few countries have established Colleges of Medical Genetics. Only this last year was the American College of Medical Genetics established, the Canadians did so earlier. It is necessary for societies, in this golden era of genetics, to establish this role for genetics in medicine.
Finally, this is a matter which I believe has not yet become problematic in countries other than the United States, and possibly Canada. Judges, have virtually no knowledge of human genetics, in fact they may have well selected law because of their dislike for science. They have a very poor comprehension of the subject, including not only human genetics but also science, biostatistics and epidemiology. As a consequence the most remarkable rulings are found in the United States on this subject, or on other subjects where judges will rule as inadmissable evidence which clearly should have been admitted, or in fact do the opposite. I would now like to consider more the general ethical and legal aspects.
Reality and Expectations
In the United States, the Human Genome Initiative at the National Institutes of Health and similar initiatives taken elsewhere and abroad, are expected to result in the location and probable cloning of virtually all single genes leading to serious genetic disease by the year 2,000. Already enormous advances in some of the more common monogenic disorders have occurred including cloning of the genes for Cystic Fibrosis, Duchenne/Becker muscular dystrophy, Fragile X syndrome, Huntington disease, and many others. These advances have already provided direct diagnostic tests based on DNA analysis as well as carrier detection tests and prenatal diagnosis, as well as developing opportunities for preimplantation diagnoses. Huntington disease serves as an outstanding example of a disorder that took some 10 years to clone the gene after its original map location was found and to recognize this gene's unique aberrant repeating motif (5). In the past, physicians would be puzzled for months to years in trying to diagnose Huntington disease, especially in the absence of a definitive family history. Now, a new rapid and precise diagnostic test is in the process of being made available to symptomatic individuals. The same test is, of course, possible on asymptomatic individuals, but raises serious questions about the advisability of testing in the absence of available treatment. Testing of individuals with no symptoms or signs may result in the provision of an ominous prognosis for this neurodegenerative disorder, resulting in early loss of faculties, dementia, vegetative existence, and early death. There is considerable concern about such "no hope" predictive testing and a major consensus that any such efforts should be made only against the background of a fully developed program with intensive and extensive psychological and genetic counseling support.
For other disorders, such as cystic fibrosis and the Fragile X syndrome, opportunities to precisely determine the carrier state of healthy individuals introduces questions concerning population screening for disease carriers. Beyond the technical issues are those that focus on the appropriateness of such testing, the minimum age at which tests could be offered, the appropriateness of testing only in early pregnancy, the psychological consequences (e.g., stigmatisation), the availability and accessibility to trained counselors, public understanding, and questions of public policy, ethics, and cost.
The ability to analyze single genes within single cells has been successfully applied to the fertilized ovum not only for detection of gene mutations (e.g., cystic fibrosis) but also for sex determination. This relatively straightforward procedure of preimplantation sex diagnosis was specifically developed for couples at risk of having male offspring with sex-linked diseases. This entirely appropriate approach has been successful and healthy females have been born to mothers at risk for sex-linked diseases as well as for those at risk of bearing a child with cystic fibrosis.
One unfortunate application of these developments was the announcement of a "gender clinic" in England (6). The aim of this clinic is to provide gender selection through preimplantation diagnosis for couples seeking to ensure that they have one child, for example, of each sex in their composite family. In cultures which prize male above female births (e.g., China and India), no surprise is likely about majority choices. Indeed, in India, following the development of first trimester prenatal diagnosis, early abortion has been used as a means of sex selection. Given the temptation for financial gain from these technical developments, strict and early promulgation of regulations are necessary and already overdue. Clearly, given the right to procreate, couples could easily claim the additional right to select the sex of their future child. Elsewhere the question has been posed whether these developments relate to "the rights of man" or the thin edge of a "eugenic wedge"? (6).
Legal and Ethical Issues
A host of legal and ethical issues have emerged as a consequence of advances in the "new" genetics. Only a few have been selected for consideration here. Privacy and Confidentiality
A considerable body of enacted or pending legislation in many individual states in the United States (7) has achieved or is attempting to achieve statutory requirements that ensure informed consent in genetic testing while protecting the confidentiality of genetic information. The U.S. Congress is in the process of considering the "Human Genome Privacy Act". The American Society of Human Genetics has issued a statement on genetics and privacy and whose 7 quintessential points have been summarized by Reilly(8) as follows:
1. Proceed on the premise that unauthorized disclosure of genetic data to third parties may seriously harm the individual who has been tested.
2. Determine who should be authorized to collect genetic information, how it should be stored, how it may be linked to other data, who should control access to it, and how such data may be used.
3. Develop rules that clearly define the permissible and impermissible uses of such data by third parties, such as by third parties, such as insurers, lawyers, and school systems.
4. Place the burden on those who would use genetic data to limit access to insurance, employment or other social institutions to provide scientifically rigorous justification for that decision.
5. Recognize that it is important to permit qualified researchers with legitimate protocols to gain access to genetic data banks so long as the information therein is studied anonymously.
6. Characterize the violation of genetic data banks and wrongful collection, use, or dissemination of genetic data as a criminal act and, also, create civil remedies for persons harmed by wrongful disclosure.
7. Understand that the highest priority should be given to developing innovative efforts to educate our citizens about genetics.
One example of already enacted legislation in the state of Wisconsin in 1992 now prohibits both insurers and employers from requiring or administering a genetic test or the results of that test, without the subject's consent (9). The Canadian Privacy Commission also recommended legislation aimed at prohibiting insurers from using genetic information.
Natowicz et al (10) define genetic discrimination "as discrimination against an individual or against members of an individual's family solely because of real or perceived differences from the "normal" genome in the genetic constitution of that individual. Various examples of genetic discrimination have been published and include circumstances in which insurance is denied to an asymptomatic individual with the genotype for hemochromatosis (in contradistinction to one suffering from this disorder).
The two major potential areas of genetic discrimination are in employment and insurance. Employment discrimination could occur when an individual was denied work simply because of his/her increased likelihood of developing a genetic disorder. The employer's concern would focus on problematic productivity, absence and, less frequently, potential occupational hazards for those genetically predisposed to specific toxic materials. In general, life insurers have considerable latitude in requiring genetic tests, although to date, few consumers have lodged formal complaints with insurance commissioners in the United States. State insurance commissioners also seem to have given little consideration to the role of genetics in life insurance underwriting (11). Certainly, for many years, life insurers have used genetic information in their underwriting in matters relating to predisposition to illness. The insurance industry argues that prohibition or limitation of their use of genetic tests would result in improper application of risk classification, principles which could ultimately lead to adverse selection. Moreover, they have emphasized that such prohibitions might render insurers extremely vulnerable to fraud. In addition, any limitations the insurance industry argues, might give some individuals with unfavourable genetic predispositions preferential treatment over healthy individuals. Thus far, the insurance industry points to a lack of evidence that people at risk forgo genetic tests because of their fear of resulting adverse insurance decisions. The contrary experience can be confirmed by many geneticists who have witnessed the chilling effect on patients having genetic tests that might reveal "preceding conditions" not covered by insurance. At least in the United States, the "Rehabilitation Act of 1973 and the Americans with Disabilities Act of 1990" offer some limited protection against genetic discrimination. In the United States, some states have enacted laws that specifically restrict the use of genetic information by employers or insurers. e.g., Maryland (12). The state of California not only banned discrimination on the basis of heterozygosity for any genetic condition (13), but passed model legislation restricting the use of genetic tests for making decisions concerning employment, insurance eligibility for group life and disability, and eligibility for health insurance (14). This bill was, however, vetoed by the Governor of California!
Commercialization of Clinical Diagnostic Genetic Laboratory Services
The lucrative genetic diagnostic test market has been discovered by industry during the past decade. Biotechnology company projections have estimated revenues approximating 166 million dollars by 1996, and have launched major efforts to capture this market in the United States. Numerous consequences are now recognized from their extremely aggressive marketing which has come to threaten the actual survival of academic-based genetic diagnostic laboratories (15, 16). The first florid untoward consequence of commercialization was the development and marketing of unapproved tests. For example, one company in particular introduced a 48 hour prenatal diagnosis chromosome test (by fluorescent in situ hybridization) before it had been published, peer-reviewed, or assessed in any formal trials. Company geneticists with stock equity and obvious conflicts of interest, produced marketing material that claimed "accuracy equal to that of traditional cytogenetics" (17). Only these company geneticists assessed this product allowing claims of accuracy exceeding 99% to go forward into the public domain. Only now, some years later, do we recognize, that the detection rate of Down syndrome by this 48 hour prenatal test is only between 70 and 73%. Such claims were advanced primarily for use as a sales and marketing "door opener" where representatives would literally gain access to the physician's office, bypassing the traditional teaching medical centres. Obstetricians, unaware of the false claims, and unable with their non-technical background, to assess the scientific validity of the work, rapidly fell prey to the aggressive sales representatives. It was no surprise, therefore, that an important error in prenatal diagnosis was made by this company using their 48 hour test as published in the New England Journal of Medicine (18). Despite stern warnings and published position statements by regional genetics groups throughout the United States, this company has continued their testing program. Moreover, from the beginning, they failed to advise either patient or doctor of the research nature of their test, never obtained informed consent, and charged for their services even though decisions relating to abortion were not advised for this test which promised instant gratification. Marketing of these tests directly to physicians unable to interpret these or more complex DNA test results has led to patient abandonment. In these cases, physicians have been unable to explain the complex test results and patients have sought out the help of geneticists in academic centres. The commercial companies have also employed individuals with Masters Degree level education in genetic counseling who practice medicine, largely by telephone. No direct physician oversight has been provided in these companies.
Another commercial dimension, completely unexpected, was the nationwide offering of a specific genetic carrier test by a commercial company before clear knowledge had developed about the implications of specific mutations for the disease in question (Gaucher's disease). This instance represented an effort by a commercial company to set a required standard of practice without appropriate consultation in the genetic community.
Considerable concern exists about the appropriateness of industry as a site for highly confidential genetic analyses. Against a background of unethical conduct (National Health Laboratories paid a fine of $110,000,000, and another company, Metpath, has paid $40,000,000 - both for fraudulent billing), the lack of institutional ethics committees, institutional review boards, and outside review boards, and no traditional ethical background for the practice of medicine, industry is clearly regarded as an inappropriate site for genetic disease studies.
DNA banking is especially important in this regard where company closure, mergers and changes of direction are common. No formal contractual and other proprietary documents have been developed to secure the safety, privacy, and confidentiality of DNA samples banked on behalf of individuals, living or dead. Questions relating to the heritability of such samples remain unsolved and research use of such samples remain possible without legitimate consent. Reilly (19) has identified at least 4 operating kinds of DNA banks in the United States:
1. Academically-based repositories largely for research purposes.
2. Commercial DNA banking services for both researchers and individuals.
3. State-based DNA forensic banks for assistance in the resolution of violent crime.
4. DNA banks in the military for the identification of human remains.
Reilly (19) has also emphasized key privacy issues including the assumption of control of a DNA sample upon the death of a depositor, right of access by relatives, and questions concerning the disposition of the sample upon dissolution of the company. In commerce today, at least in the United States, there is DNA banking, as well as storage of DNA personal and family data in settings in which the profit motive is king and in which a potential threat exists to an individual's right of privacy.
In the development of legislation that incorporates all the implications of genetic testing including privacy, confidentiality, and genetic discrimination, self-evident ethical principles need to be applied (20, 21). Fundamentally beneficent in its orientation, any such legislation should guarantee the respect and dignity that should be accorded every human being and the inviolability of the human body and the integrity of the human species. Eugenic practices including gene selection, gender selection, or selection of physical or racial traits could be banned. Germline gene therapy which might alter the human genome could be banned. Body parts, tissues, or cells should not be the subject of inheritance rights and regulations should be promulgated to prohibit the patenting of such tissues or cells or genomes. The sale of such body parts, cells, or genomes should also be specifically prohibited. Informed consent requirements require establishment and enforcement in the context of genetic studies. Extensive formulation of rules and regulations to secure patient privacy and confidentiality require enactment together with criminal and administrative sanctions relative to anticipated failures in the application of the new knowledge gained from modern genetics. Only by virtue of the establishment of laws beneficial to the individual and his or her genetic identity will it be possible to secure the benefits that will continue to accrue from our newly found knowledge.