Richard R. MacMahon, Ph.D.
OBJECTIVES
To develop in each student an understanding of the ethical issues surrounding the information emerging from genetic research and the developing concerns for fairness in the use of this new genetic knowledge.
Our increased genetic capability over the last thirty years has raised many ethical concerns. Many new discoveries of gene structure and function have come either directly or indirectly from the Human Genome Project. This project was conceived and implemented in the 1980’s as an attempt to map the entire human genome, and as a result many new genes and alleles of genes have been discovered (Kevles and Hood, 1992; Suzuki and Knudtson, 1990). We are still trying to understand and interpret all of this new information. Unfortunately, because we do not always do this wisely or fairly, some complex ethical issues arise and need addressing. This was realized and commented on as early as 1990 (Hall, 1990).
The biggest problem seems to be that we try to apply knowledge before we fully grasp the details of what we have learned (Suzuki and Knudtson, 1990). The detection of a gene, once described and worked out, is often more accurate than our knowledge of how the gene functions. Thus we find people denied jobs simply because they carry a particular allele, such as the allele for Huntington disease, hemophilia or breast cancer. The allele may be present only in the heterozygous condition, and the job applicant turned down for “intermediate deficiency” of that gene without determining if the actual condition can or will occur. (Suzuki and Knudtson, 1990) Important ethical issues arise from the ability to screen for particular alleles, without fully understanding the implications of the presence of the allele (Beardsley. 1996). For example, may an individual be forced to provide a blood sample as a condition for employment? If the sample is requested in order to test for drug use, may it also be used as a screening device for genetic defects?
Another ethical problem arises with the recent ability to determine many of the characteristics of the fetus, including gender and possible genetic disorders. We can now also quite accurately use DNA sequencing or “fingerprinting” for positive identification of individuals forensically and in cases of disputed parental identity. These increased capabilities have generated the ethical issue involving the termination of pregnancy: Has a genetic disorder been detected? What genetic disorder, one that is life-shortening and painful such as Tay-Sach’s disease? Is the fetus of an unwanted gender? Or is the termination for the convenience of the parents? Termination of pregnancy is induced abortion, which is probably the most generally debated ethical issue of our time in society.
Another concern is the right of self-incrimination: May an individual be forced to provide his own blood to the government for testing in criminal or civil cases, or for any other use? Or does this contradict the right against self-incrimination? So far, as in the O. J. Simpson case, it seems as if the suspect is required to provide a blood sample, as an extension of the regular laws regarding fingerprints. What are the victim’s rights in cases involving blood evidence?
What is happening to the concept of physician-patient confidentiality? Who should have access to the results of blood tests? (Gorman, 1996). Should an adult automatically be told by their physician that they have a detected genetic disorder? What about Huntington disease, which usually does not show symptoms until a person is well into child-bearing age and may already have produced children? Some people who had parents with Huntington disease do not wish to be told if they carry the allele for this disorder (Wexler, 1990).
We must also be concerned with the question of individual rights as we grow increasingly more proficient in the use of genetic technologies. In the near future, will a perspective employee be required to submit a blood sample? What happens to a person who is carrying the genes for a genetic disorder? Is this legitimate grounds for denying employment and/or health insurance? May a person be denied coverage or suspended from a health plan if there is DNA evidence of a genetic disorder? Is carrying the gene for a genetic disorder really a “pre-existing condition” as is claimed by some insurance companies? Or is it really only the potential for a condition? Will the future see an attempt to breed out of the population deleterious genes? Will forced sterilization for “genetically inferior” individuals become the law of the land? These are all questions that have been raised in one context or another as parts of some serious attempts to influence the genetic composition of society. (Kevles, 1986; Herrnstein and Murray, 1994; Gould, 1981, 1995; Suzuki and Knudtson, 1990; Reilly, 1991).
“Wait a minute!” you say. “These are all rather fanciful examples. They could not really happen!” But most of these examples have already occurred. Several women already have been discriminated against by insurance companies and HMO’s because of possible breast cancer (Beardsley, 1996; Smith, 1996). Medical files that used to be confidential between a physician and patient are becoming increasingly available to employers and insurance companies through access by computer (Gorman, 1996). A bill currently is being debated in Congress that would restrict immigration based, in part, upon IQ. One of this bill’s major references is the book by Herrnstein and Murray (1994) that expounds the cause of racial differences in IQ.
The other day I saw a sign at a large discount store announcing that they conducted random tests for drugs, and drug users should not bother applying for a job. Usually the tests are simple urine tests, but if the company has a blood sample they are testing for drugs, what else might they test for without informing the employee? Recently two marines were court-martialed for refusing to donate blood and tissue samples. (Anon, 1996) Their reason for refusing was simply that they could not be sure how these samples would be used in the future. (Gorman, 1996).
There was a well-intentioned screening campaign for sickle-cell anemia developed during the early 1970’s. But the situation soon “turned ugly”. “Perfectly healthy carriers of the trait were led to believe that they were sick”. Soon some states had defined the heterozygous condition as a disease. Some insurance companies began to deny coverage to heterozygotes on the grounds that “they had a pre-existing medical condition”. These people were also denied jobs in certain fields. The ultimate solution suggested by scientists was that these heterozygous people forgo having children—an idea that was quickly interpreted by the black community as a form of racial genocide. (Rennie, 1994).
Attempts to use genetic information medically frequently involve intentional alterations in an organism’s genetic composition. Unfortunately, we do not always know what the results of our attempts at genetic engineering will be. Unexpected results in the future may cause problems that we have not anticipated or cannot even imagine. Consider the following example. In one case, mice were manipulated in a genetic recombinant experiment by “knocking out” a gene essential for the synthesis of nitric oxide, a neurotransmitter in the brains of mice (and also of men). Attempts to block production of this neurotransmitter resulted in producing some very ferocious male mice, (females were not affected), whose behavior was six times more aggressive than normal mice. These males also engaged in excessive and inappropriate sexual advances to females, in what can only be described as rape. (Toufexis, 1995).
A similar experiment on mice, involving the enzyme monoamine oxidase A, led to similar results. Here the young male mice that were deficient in the enzyme showed extremely aggressive behavior and other signs of neural abnormalities. They constantly clasped their female litter-mates. (Hilchey, 1995) The implication of both of these reports is that similar conditions exist in humans and that these enzyme deficiencies are responsible for these types of aggressive behavior. There are known rare, abnormally aggressive human males who lack normal amounts of MAOA. It is suggested that a drug therapy can be developed to treat these individuals.
Is it fair to raise or lower people’s hopes with reports of new gene locations and structures, and of new gene therapies? It seems every week there is another report of some new gene elucidated or of some new gene therapy in the news. Recently there have been reports of a genetic test for the breast cancer gene (Beardsley, 1996a) and a gene therapy for baldness (Hilchey, 1995a).
There have been many other reports of attempts at gene therapy. The attempt to correct cystic fibrosis by inserting the correct gene with a viral inhalation spray has probably obtained the most publicity. But the fact remains that gene therapy has so far not been successful. And every time we publish another account of a gene or a gene therapy we raise the hope for a cure in those afflicted individuals.
The gene therapy field is dominated by commercial companies that develop and market these therapies (including companies in biotechnology, drugs, agriculture, diagnostic laboratories and even HMO’s). Many of these companies seem more interested in their profit margin than in the efficacy of their gene therapies (Kolata, 1995b). To date there has only been one instance where gene therapy has been successful. This was an attempt to insert the correct gene for adenosine deaminase into white blood cells. The result was the restoration of the immune system (Anderson, 1995). And from time to time the patient must still return for booster treatments.
But there has also been a recent report of a genetic cure for baldness (Hilchey, 1995a), which stated that liposomes with the correct gene had been shot into the skin of hairless mice. The liposomes then gave up the correct genes to follicular cells and hair growth was restored to a near-normal condition. Great news for balding people! Except that the experiment was conducted using mice and the last paragraph of the article stated that mouse skin absorbs liposomes much more easily than human skin. Again are we raising false hopes?
In a more imaginative vein, there are also reports of DNA being used in the future as a computer (Kolata, 1995a) and a recent report on redefining the gene for femaleness (Angier, 1994). There is also another report on the identification of the gene for dysautonomia. This work was funded by a small foundation made up of the parents of children afflicted with the disease, parents who desperately wish for some progress on an affliction which is seriously impacting the lives of these families (Kolata, 1996).
Below I have included in Table I a list of gene therapies undergoing clinical trials in 1995. Just one year later, this list would seem to be woefully out-of-date. But it gives a good idea of the breath of areas and scope of research going into gene therapy. (Anderson, 1995).
Table I. Diseases Being Treated In Gene Therapy Trials
(Anderson, 1995)
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¥ Cancer (Including melanoma, renal cell, ovarian, neuroblastoma, brain, head and neck, lung, liver, breast, colon, prostate, mesothelioma, leukemia, lymphoma, multiple myeloma)
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¥ Severe combined immunodeficiency (SCID)
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¥ Cystic Fibrosis
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¥ Gaucher’s Disease
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¥ Familial Hypercholesterolemia
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¥ Hemophilia
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¥ Purine nucleoside phosphorylase deficiency
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¥ Alpha-1 antitrypsin deficiency
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¥ Fanconi’s anemia
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¥ Hunter’s syndrome
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¥ Chronic granulomatosis disease
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¥ Rheumatoid arthritis
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¥ Peripheral vascular disease
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¥ AIDS
Another ethical problem involves changing the cells of the germ line (stem cells which divide to produce sperm cells). It is one thing to change somatic cells in a patient’s body. The result is confined to that one individual. But when the germ line cells are changed all subsequent offspring will show the effect. Stem cells of mice have recently been successfully changed (Kolata, 1994). But since we are not entirely sure of the effects of changing germ line cells, there are grave doubts being raised over these experiments (Kolata, 1994a). Might changes in human germ line cells be used to attempt to breed a “super race” of men? This harks back to experiments performed in Nazi Germany. Will future prospective parents seek “designer sperm cells”? If this technique of changing germ line stem cells can be extended to humans, it raises some very basic ethical questions.
It is easier to genetically change plants and microbial organisms than it is to alter the genetic composition of mammals. But here again ethical questions are raised. A plant has recently been genetically engineered to take up mercury from the environment (anon., 1996a). But this has only been accomplished in the laboratory and we do not know the effects of releasing this altered genome into the environment. The effect might be one entirely unexpected.
In one carefully controlled experiment, oilseed plants were genetically engineered with a gene for resistance to an herbicide. These plants were then allowed to grow with a native related plant, a weed called wild mustard. The result was that there was hybridization and the weed ended up with the gene for resistance to the herbicide. In this case the experiment was closely controlled, all the plants were destroyed and there was no harm done (Beardsley, 1996). However, this experiment does show how easily genes can escape from genetically engineered crops into the surrounding natural environment.
The Bt gene is a gene found in a bacterium that codes for the production of a protein that is a natural insecticide. This gene has recently been engineered into corn, cotton and potatoes. This would mean that we could have plants with a built-in insecticides, and this would greatly reduce the use of harmful chemical insecticides in the environment. But very quickly two very disturbing problems seem to be arising. One, will insects develop a tolerance for this protein? This seems to have occurred in some trials of engineered cotton in Texas. And two, will the Bt gene “escape” into the wild, weedy relatives living in the area? If this happens will they have an advantage over native plants in that the weeds will be more resistant to insects? (Feder, 1996). Again, it seems as if we are not sure of what we are attempting.
In another experiment, a gene from Brazil nuts was introduced into soybeans intended for use as animal feed in an attempt to boost the methionine level in the soybeans. But the introduction of new genes leads to the production of new proteins. In this case one of the new proteins caused a “life-threatening allergic reaction in people”. The company quickly stopped the project (Beardsley, 1996). But here again we see an unexpected result from a genetic engineering.
There have been several incidents in the past few years of people becoming sick, and some actually dying, from hemorrhagic colitis. This disease is a severe form of diarrhea and is caused by the
Escherichia coli
bacterium, strain O 157: H7. But
E. coli
is common and normally present in large numbers in the intestinal tract of mammals. What caused this strain to become so virulent?
There is another bacterium named
Shigella dysenteriae
. This bacterium produces Shiga toxin which causes diarrhea. The gene for Shiga toxin has jumped from
Shigella
to
E. coli.
When present in the much more common
E. coli
the Shiga toxin gene causes the production of the Shiga toxin in large quantities. If undercooked meat, especially ground hamburg with its large internal surface area, is eaten the
E.coli
in the hamburg ends up in the intestine. If it is carrying the gene for Shiga toxin, hemorrhagic colitis will result (Hilts, 1996).
This seems to be a case of natural genetic engineering. But the consequences for man have been severe. Many people have been stricken with hemorrhagic colitis and a few have died. Remember the Jack-In-The-Box incident of 1993? Four children died and many people were stricken. In July, 1996 the same strain of
E. coli
caused extensive food poisoning in Japan, with at least four deaths reported (Anon., 1996b). A later report sets the death toll at 100 and the number stricken at 8700. It was reported that there are 100 new cases per day (Anon, 1996c)
One of the genes in humans that has been identified is the apo E gene. There are four alleles for this gene and an individual inherits one allele from each parent. People with two copies of the apo E4 allele have an increased risk for heart attack of from 30% to 50%. Thus physicians are increasingly including identification of this gene in blood work for heart patients. However, apo E4 is also an indicator for Alzheimer’s disease. If a person has two copies of the apo E4 allele there is a 90% chance of developing Alzheimer’s disease by the age of eighty (Kolata, 1995).
And thus is posed another serious ethical dilemma. If a physician tests for apo E and finds two copies of apo E4 what does he or she do? Do you tell an otherwise normal 50 year old patient that they have a 90% chance of developing Alzheimer’s disease by the age of eighty? Should you tell someone that in all probability they will develop a degenerative brain disease for which medical science has not yet developed the ability to alter or slow the course of the degeneration? We are becoming very adept at identifying genes and linking them to disorders, but we can’t always treat the disorder. Should the physician simply remain silent until the onset of the degenerative process? Does knowing that you carry two copies of the apo E4 allele cause stress? And can this stress contribute to the onset of Alzheimer’s disease? There are many facets to this ethical problem.
One other area where gene identification has been used is in an attempt to predict behavior. Several years ago it was suggested that a large proportion of those males with an extra Y chromosome (the XYY condition) were in prison for violent crimes (Kevles, 1985). Thus the extra Y become known as the “criminal chromosome”. Subsequent work showed this analysis to be completely spurious. There is no basis in fact for asserting that an XYY male is prone to violence and crime. And yet this idea seems to persist in our culture (Gibbs, 1995). Other behavioral studies, especially the study of monozygotic twins done at the University of Minnesota, have shown “a strong genetic contribution” to many traits including religiosity, political persuasion, leisure-time interests, sexual preference, intelligence, personality types and other traits. But the Minnesota study seems highly flawed by its selection method (Horgan, 1993).
The point is this. If behavioral traits are genetic, then we are possibly in a position to identify the genes involved. And if we identify these genes we may contemplate eliminating the undesirable genes from the population. But who decides which genes are undesirable?
We already know that there are some links between “brain chemistry, heredity, hormones, physiology and assaultive behavior” (Gibbs, 1995; Blakeslee, 1996a). For example, physically aggressive men have higher levels of testosterone. Also—seratonin has a calming effect on the brain. Men with low levels of seratonin are inclined to impulsive aggression. See the discussion above concerning MAOA (Hilchey, 1995). However, these studies are merely suggestive of what is happening in the brain. There is still much work to be done to definitely link physiology to antisocial behavior.
While these studies are as yet preliminary and tentative, this fact has not stopped other people from suggesting that people with an extra Y chromosome or with low levels of MAOA be treated as potential criminals. They even went so far in Boston as to begin screening new-born babies for the XYY condition. This was stopped when subsequent studies failed to find a correlation with aggression (Gibbs, 1995). However, the potential is there for a eugenics program that might have severe consequences in society in the near future. (Kevles, 1985)
The ethical considerations of all of these examples and possibilities are enormous. And these are considerations that all students need to be aware of, for in the near future we will, as a society, be asked to decide on the limits of many of these new genetic procedures. Several ethical issues that we have considered here are:
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1. Is it fair to raise or lower people’s hopes?
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2. Is it ethical to change the germ cell line?
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3. Are we releasing genes unwittingly into the environment?
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4. Are we rushing to judgment before we fully understand the implications of what we have discovered?
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5. Are we violating an individual’s legal rights as well as their right-to-know and their right to privacy/confidentiality?
