The process of unraveling the mysteries of the human genome creates enormous possibilities in the world of science. Knowing where on our chromosomes a specific gene lies allows scientists to look inside the human body with more intensity than any X-ray could ever achieve. By analyzing the genetic make-up of human beings, scientists can track diseases back to their most fundamental stages. In recent years, scientists have discovered two genes that play a role in the development of various kinds of cancer in both men and women. With the additional ability to test individuals for their possession of deformed copies of these genes, many ethical questions have been raised. Although the majority of objections surrounding these tests seem to stem from economic and policy issues, there still exist social concerns as well. In time, these issues will have to be dealt with, because as has become increasingly the case, scientific developments preceed, rather than follow, serious ethical and legal thought.
In a healthy body, every one of the 30 trillion cells work together to regulate the transfer of information, movement, and countless other processes. One of the most crucial functions of each cell, however, is to regulate the cell growth itself and of neighboring cells. This is accomplished by creating checks on cell growth, such that no cell is to reproduce unless instructed to do so by those cells around it. When placed in a petri dish with food, a single cell will divide until the copies begin to reach the walls and come in contact with one another. At this point, they will exhibit the property of contact inhibition and will stop growing. Cancer cells, however, "violate this scheme; they become deaf to the usual controls on proliferation and follow their own internal agenda for reproduction." Cancer cells are able to survive, despite the damage done to essential components of chromosomal DNA because they can avoid the cell's normal defense mechanism of apoptosis, or cell suicide. This measure is effective in destroying harmful mutations before divisions can cause the mutation to spread and harm vital organs. Furthermore, while normal cells have a finite life span, such that after approximately 50 to 60 divisions they become senescent, cancer cells continue growing indefinitely, and are thus called immortal.
There are two key ways in which cancerous tumors form. Within the human genome, the two primary gene classes which control cell growth are proto-oncogenes which encourage cell growth, and tumor suppressers which inhibit it. Proto-oncogenes can lead to cancerous growths if mutations in the gene cause it to produce too much growth-stimulatory protein, or a hyper-active form of it. Tumor suppresser genes can also lead to cancerous cell reproduction when mutations make the gene incapable of putting the breaks on reproduction. Normal activity of a proto-oncogene can thus be cancerous if the tumor suppresor genes are rendered incapable of carrying out their function of regulation. With this classification, it is easy to see how one might use gene therapy and recombinant DNA techniques to introduce into the system a fully-functioning tumor suppresser gene. Presumably, if cells are reproducing at a normal rate and are merely incapable of being stopped, inserting into the cell a gene that can produce tumor suppresser proteins which will fight excessive growth might regulate the system. This gene itself would have to be regulated properly as well, and presently this method has not been made to be effective.
Though problems have been identified with this method, it is clear why the recent discovery of two tumor suppresser genes, BRCA1 and BRCA2 (Breast Carcinoma 1 and 2), has raised the hopes of many in the medical community of finding a cure for the diseases. Originally thought to be responsible only for hereditary cases of breast cancer, the range of cases in which mutated BRCA1 and BRCA2 genes have led to cancer has increased. The discovery of the BRCA1 gene, located on the 17th chromosome, was reported in the October 7, 1994 issue of the journal Science. In sexual reproduction, an offspring is endowed with two copies of each gene, one allele coming from each parent. The value of having two copies is that should one mutate over time, a second copy can still maintain proper functioning. When one parent passes on a defective BRCA1 gene, however, this cell "does not have a `backup' if the other copy becomes altered." The inheritance of a mutated BRCA1 gene accounts for a predisposition to develop certain cancers, as the increased likelihood of a second mutation leading to a lack of functionality may lead to an inability to suppress tumor growth.
This is similar with the second breast cancer gene, whose discovery was reported in the December 21, 1995 issue of the journal Nature. P. Andrew Futreal of Duke University Medical Center was one of the primary investigators searching for the gene that was eventually located on the 13th chromosome. "Like BRCA1, the gene appears to function as a tumor suppresser gene," Futreal said. "The normal copy of the gene is knocked out, the mutated copy is retained, and the gene loses its ability to function normally."
Though the exact cellular function of the BRCA1 and BRCA2 genes has not yet been discovered, researchers have noticed a number of differences in the two genes. According to Myriad Genetics, one of the forerunners in the identification, coding, and development of analytical tests for the breast cancer genes, "individuals who carry BRCA1 mutations have an 82% risk of developing breast cancer by age 70 compared to a risk of approximately 10% for noncarriers. Women with BRCA1 mutations have a 44% risk of developing ovarian cancer by age 70, whereas noncarriers have a risk of about 1%." In the case of BRCA2 mutations, the risk of developing breast cancer in a woman remains the same, though: "members of families with the BRCA2 gene also seem to be at greater risk for several other cancers, including male breast cancer, prostate cancer and ocular melanoma." It has been observed that in families with a history of breast cancer, men often develop prostate cancer. Conversely, in families with a high incidence of men with prostate cancer, woman often develop breast cancer. Due to this relationship, researchers have begun to search for specific mutations that lead to the development of prostate cancer by chromosome walking and mapping the 13th and 17th chromosomes. The logic for this is simple. In cell division, when two genes are closely positioned on a single chromosome, and are thus not likely to cross over, they are said to be linked. As those genes which are involved in the development of breast cancer and prostate cancer appear to occur together, and can logically be said to be linked, it makes sense to begin chromosome walking at those identified spots on the 13th and 17th chromosomes.
One crucial point to note is that inheriting a defective BRCA1 or BRCA2 gene does not affect one's chances of developing a type of cancer because the mutation itself somehow codes for a cancer causing protein. Rather, an individual with one defective copy is as fully-functioning as an individual with two, because the tumor-resisting proteins are still being produced. Over time, however, mutations do gather in the healthy gene. This inevitably occurs in every cell each time the DNA is replicated. Thus, mutations will occur in all individuals, and genes will become defective in everyone. It just so happens, however, that being tumor suppresser genes, BRCA1 and BRCA2 are crucial in the process of regulating the body's processes. When enough mutations occur in the inherited, mutated allele of one of the breast cancer genes, and at least one mutation occurs in the second, previously perfect allele, the cell will lose the ability to produce tumor-suppressing proteins and this will lead to cancerous growth. However, this is not limited to individuals who inherited a defective allele. If enough mutations occur in an individual who inherited two proper copies of the genes, that individual would also be susceptible to cancerous growth. Possessing a defective copy of one of the breast cancer genes is therefore neither a necessary, nor a sufficient condition for the development of ocular melanoma, or breast, ovarian, and prostate cancer, it merely creates a special disposition towards them.
Once the discoveries were made, researchers and companies became extremely active in putting the knowledge to use. Myriad Genetics, Inc. was the first team to complete sequencing of the BRCA1 and BRCA2 genes. With this head start, they also developed that first comprehensive test which they promptly patented under the name BRACAnalysis. The Myriad test is more complete than other tests as it does a complete examination of the individual's genes to discover each and every error that occurs. "In the BRACAnalysis process, Myriad performs over 80 separate PCR amplifications and examines more than 16,500 DNA base pairs." In order to be tested, the fee for such a complete analysis is $2,400. Although Myriad will then provide testing for a specific identified genetic mutation in susceptible family members for $395 each, and does have an assistance program, the cost for this testing is quite steep.
With the availability of testing, ethical questions inevitably followed. When speaking at Dartmouth College, Dr. C. Everett Koop, former United States Surgeon-General, and Director of the Koop Institute, commented on the importance of privacy in dealing with questions of health. When privacy is breached, and it is revealed that a woman has a greater than 80% chance of developing breast cancer, or that a young man will develop Huntington's disease, this individual immediately becomes "unmarriagable, unemployable, and uninsurable." Taken in reverse order, Dr. Koop's words can help guide us through three of the most difficult concerns raised by this new technology.
When dealing with testing and the privacy of patients, the problems involving health insurance and employment go hand in hand. In order to discuss issues of privacy, and testing, however, it is first important to identify who ought to be tested. According to the American Society of Clinical Oncology, "cancer predisposition testing [should] be offered only when: 1) the person has a strong family history of cancer or very early age of onset of disease; 2) the test can be adequately interpreted; and 3) the results will influence the medical management of the patient or family member." With the high cost of testing, on whose shoulders ought the payment fall? To some, it seems quite clear that as the test is being done for the benefit of the individual, it is the individual's responsibility to pay. On the other hand, however, any operation undertaken by an individual that is covered by an insurance company is similarly benefiting solely that individual. In fact, the entire purpose of the health care system is to collect a certain amount of money from many individuals into a collective pool in case one individual needs a medical procedure.
It would seem, therefore, as though it were the insurance companies' responsibility to cover the tests for those at risk. In a recent article in The New York Times, however, Gina Kolata tells the story of a woman who tested positive for a mutated breast cancer gene. She approached her insurance company with a claim for the immediate surgical removal of both of her breasts. At first she did not tell them of the test results, but merely said that her family had a history of breast cancer. The woman's claim was denied as the insurance company does not cover preventative medicine. She then asked her doctor to submit the results of her test, at which point she was denied again. As she possessed the defective gene before taking out her insurance policy, it qualifies as a preexisting condition, and thus was not covered under her plan. When the woman proceeded, paying for the operation out of her own pocket, breast tissue examined subsequent to the procedure was found to contain a cancerous tumor that had not shown up on her mammograms.
When the Kennedy-Kassenbaum bill was passed into law, it became clear that the Federal government was interested in addressing these concerns. The law stipulates that "if an individual was in [a group medical plan] for at least 12 months and had a genetic condition diagnosed in the past 6 months, a new insurer cannot use that genetic information to deny or limit coverage." This law has both its successes and failures. It is certainly a step in the right direction to protect some of the more vulnerable members of our society with regards to health insurance. In creating this provision protecting people with genetic conditions, it prevents them from being thrown out of their current policies. The failure of the bill, however, is that while people cannot be denied coverage, the bill does not mention a cap on premiums. One problem this has created is that when genetic test results are released, insurance companies raise premiums to levels that workers cannot afford. This has the effect of denying coverage, and in response, several states have passed laws "preventing health insurance companies from charging people more because they have a genetic mutation." Furthermore, the Health Insurance Portability and Accountability Act of 1996 will take effect on a Federal level July 1, 1997. "The bill prohibits employers or insurers from discriminating by charging higher premiums or denying coverage to employees or their families based on genetic information."
It is the hope of those involved that once men and women can no longer fear discrimination when they receive their test results, the entire process will move more swiftly. Currently, many people who receive test results are forced to withhold the information from their doctors for fear of having it placed in their medical records. While research centers can maintain the anonymity of their participants, treatment centers do not have such a luxury, so out of fear, many women use aliases when being tested in order to protect against future discrimination, but are then unwilling to participate in long-term studies that might be of real benefiting in helping doctors single in on a cure. The American Society of Clinical Oncology statement reads: "To the greatest extent possible, genetic testing for cancer susceptibility should be performed in the setting of long-term outcome studies." The logic behind this is that "the only possibility of learning if there is a way to prevent cancer in women who are predisposed . . . is to do long term studies."
On the other hand, the issue is not so clear as that. There is a reasonable justification for why health insurance companies which have many other members to cover, as well as employers who often need long-term workers, would want to know an individual's medical records. As a part of a health insurance plan, just like a car insurance plan, premiums depend upon the risk group you fall into. New drivers who are very young pay extremely high premiums because statistics show that they get into many ( often alcohol-related) accidents. In the same way, one might argue that an individual who is predisposed to developing cancer, a disease requiring frequent tests and expensive procedures, would place an unfair burden upon those who do not have the defective gene, and therefore are significantly less likely to require such treatment. It might also be important for an employer to know upon hiring a new executive that there is an overwhelming chance that that individual will develop an illness which will cost the company a great deal of money. The logic behind this goes back to the way insurance companies are run, because many companies can afford to offer health care to their workers by paying the premiums themselves. If an insurance company wants to charge higher premiums for someone with a certain genetic predisposition, it would not seem right to place the blame on the employer to pay the higher cost of the premium as that would place an unfair burden upon him. A second factor when dealing with employers is separate from the issue of insurance companies. Many times, a company will see a new employee as an investment. They will spend a great amount of money, time, and effort training and incorporating the new worker into the company. Other times, someone is hired for a very important position such as CEO of the company. In these cases, it might seem reasonable for an employer to want to know everything about the new acquisition, including any possible future medical conditions that might get in the way of his/her work, and prohibit the employee from fulfilling this tasks assigned and expected.
With regards to Dr. Koop's claim that black-balled individuals become "unmarriagable," a man or woman who tests positive for one mutation must face difficult choices not only about their own health, but also about their reproductive future. Though a man is rarely at risk for breast cancer (Note: a positive test result for a mutation in the BRCA2 gene can increase this risk), Myriad suggests that "a man who has a mother or sister with a known BRCA1 or BRCA2 mutation may want to know if he has the mutation, too. If he does, each of his children has a 50/50 chance of inheriting the mutation." As many forms of cancer are treatable, it may be difficult to see entirely the problems that public knowledge of an individual's genetic predispositions might cause. With a debilitating disease such as Huntington's, however, it is clear that an individual might have increased difficulty interacting socially once privacy is breached. People fear being treated differently by family members and friends who are aware of the genetic condition. Another concern is that knowing that one possesses a defective gene may lead to stress for the individual as well as the family. David Sidransky who advises OncorMed, a company in competition with Myriad, argues that such increased stress and trepidation may result, but "these issues don't compare . . . to getting metastic breast cancer and dying from the disease," a result he feels might eventually be prevented through testing.
There ought not be any doubts that discovering the secrets of the human genome is an amazing thing. There are those purists who fear that any amount of tampering is too much tampering, because either nature or God created us as we are. Nevertheless, the study of genetics is generally regarded as an important step in improving the health and comfort of humankind. Similarly, figuring out the make-up of the atom was also a crucial discovery. In both cases, however, it is the treatment of the information that is so worrisome. Using their intricate knowledge of the atom, scientists created a powerful weapon whose only purpose was to destroy. Similar fears abound with regards to the possible handling of this new discovery. The recent cloning of a sheep, raising fears about the possibility of cloning human beings, is a perfect example of technology advancing far more rapidly than intellectual and ethical thought on the issue. When scientists are given the opportunity to carry out long-term studies, it is highly possible that they will develop a cure. It is how society, scientists, insurance companies, etc. will handle the information that makes this, as Dr. Thomas Murray, director of the Center for Biomedical Ethics at Case Western Reserve University calls it: "a classic ethical quandary."
American Association of Clinical Oncology, "Statement of the American Society of Clinical Oncology: Genetic Testing for Cancer Susceptibility," Journal of Clinical Oncology, Vol. 14, No 5 (May 1996): 1730-6.
Kolata, Gina. "Advent of Testing for Breast Cancer Genes Leads to Fears of Disclosure and Discrimination," The New York Times, 4 February 1997, C1-C3.
Koop, C. Everett, former U. S. Surgeon-General. "The Impact of Genetics on the Health Care in the United States," Biology 4, Dartmouth College, 13 February 1997.
Myriad Genetic Laboratories, Inc. "BRACAnalysis: Comprehensive BRCA1 and BRCA2 Sequence Analysis for Susceptibility to Breast and Ovarian Cancer," http://www.myriad.com/Product_Reference, (26 Feb. 1997).
"Genetic Analysis for Risk of Breast and Ovarian Cancer: Is it Right for You?" http://www.myriad.com/Patient_pre-test, (26 Feb. 1997).
"Myriad Genetics Introduces the First Comprehensive Breast/Ovarian Cancer Susceptibility Test." http://www.myriad.com/Launch_PR, (26 Feb. 1997).
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