Ann Boyd and Denise Hise
Introduction
E.B. White’s children’s classic, Trumpet of the Swan, offers a touching fantasy of a young trumpeter swan, Louis, who unlike his siblings is born without the ability to trumpet. Lacking this natural ability, Louis will never be able to attract a mate and live a complete life [1]. Recognizing this reality, his parents intervened. His father flew into a nearby town and stole a trumpet, which Louis learned to play, and thereby earned not only a living but also his mate’s heart. Stealing the trumpet compromised the integrity of Louis’ father and Louis made restitution by paying the debt for the instrument. The substitution of an instrument for the natural call of the trumpeter swan is of course what charms the reader – while one is left to ponder how many substitutes for natural abilities might lie in the hidden storehouse of genetic knowledge.
Hailed as the biological age, the twenty-first century offers through the Human Genome Project the blueprint of the human being. A map of every gene, the relationship between genetic sequence and disease is an alluring storehouse of knowledge. Unfortunately the DNA sequence does not encode moral wisdom in how to use the information. In a world of instant gratification we hope the promises of science are true, that doctors will fix that which is broken in our lives and modern medicine will give us disease-free existence for a full century. No longer resolving to simply age gracefully, our aversion to impermanence drives us to the pharmacist or plastic surgeon. We know having children is now more choice than chance as in vitro fertilization (IVF) coupled with preimplantation genetic diagnosis (PGD) allow us to ignore the biological clock and reproduce on our chosen timeline, selecting the embryo with the more attractive traits, free of any compromising abnormalities. We look forward to the not too distant future when genomic knowledge will empower us to eliminate heritable disease one embryo at a time and various intervention therapies will correct whatever we miss. It’s only a matter of time and money we’re told, until the privileged may come with high hopes to this new field of dreams.
But is the free market the only counsel we should seek? Where’s the dialogue, the oversight, the restraint? Are we equipped to make such decisions and do we have the right to determine who among us is entitled to life? The need of a paradigm for universal discussion and respectful dialogue among people in order to extract wise guidance on how to use this new genomic information could not be more urgent. The United Nations’ Educational, Scientific, and Cultural Organization (UNESCO) Declaration on the Human Genome and Human Rights uses the language of respect for persons, beneficence and justice in offering guidelines for dialogue about genetic knowledge and its putative applications. The declaration is a good start in framing ethical considerations in ways persons and nations could find useful. Protecting individual rights as a function of government will likely be interpreted in diverse ways within and among nations. If individual choice is paramount without consideration of the common good of humanity and the ecosystem, we risk allowing autonomy to trump justice. The policies and legislative process should be sensitive to individual autonomy and collective justice.
Coveting Trumpets
Given the chance, it can be presumed, science eventually will decipher the genomic code and it will be left to us to decide if we will restrict application of genetic discoveries to particular diseases and traits or use the knowledge to satisfy our most frivolous whims through physical enhancement or improvement. There will always be some level of ignorance and chance remaining, so we will never rid our species of all its ills and some of our actions may well do more harm than good. Humankind has been endowed through evolution over millions of years with a fabulous wealth of features suited to our continued survival and in the face of such decisions involving unquantifiable risks and illusory benefits, we should question our ability to better that. Historically, we have not always shown ourselves to be the most prudent of decision makers, often pursuing superficial objectives over substantive ones. We are frequently shortsighted, intolerant and resistant to change – unless of course it promises immediate gratification. Yet we purport to be on the whole good, mostly rational, and at times even creative. Perhaps a short review of our track record at attempting to ‘improve’ purebred dogs can illuminate our path or give us pause.
The prestige associated with possessing a prize-winning purebred dog has led to the selective breeding of animals with specific traits that conform to narrowly-defined standards of perfection. Seeking to perfect characteristics may bring home the blue ribbon today but are subject to change tomorrow and are not always good for the future well-being of the breed. While strength, skill and intelligence were once considered important, physical appearance now is paramount and breeders have obliged by fostering the reproduction of attractive but unhealthy animals. [2] More wrinkles on a Shar-Peis may increase the price on his head but at the cost of congenital skin disorders for his kin. The emphasis on long noses and closely set eyes in Collies may be contributing to the retinal disease that plagues these purebreds. [2] Sloping hips on a German Shepard may catch the judge’s eye but compromise the skeletal health of the breed. After many generations of selective breeding, some of these animals have trouble even walking and breathing. Our frivolous goals have compromised the overall health of purebred animals, leaving “selective” breeds suffering from heritable disorders of unknown cause or cure while the innocent motive was merely improvement.
Breeding for a particular trait requires mating between animals that share the trait; oftentimes, this is achieved through inbreeding. As in any animal, inbreeding risks a reduction of genetic diversity and fitness. Loss of heterozygosity can mean sacrificing untold genetic advantages since one functional copy of a gene is often protective and knowledge of the function of many specific genes is yet to be obtained. Breeding in loss of genetic variability merely to satisfy human desires may lead to unanticipated harm and therefore to act without knowing the consequences seems irresponsible at best. Introducing and perpetuating genetic defects for purely self-serving motivations is unconscionable. If applied responsibly, however, the power of such selection could also be used for good. Excluding affected animals from breeding programs could potentially control known diseases and overall breed health could be rapidly improved in this manner, especially if some degree of certainty could be obtained concerning unintended consequences of particular genetic interventions. But there is no certainty in life. As genomic information becomes increasingly available, the ability to eliminate whole groups of deleterious genes from a population brings with it the possibility of great good or great harm and care must be taken to ensure that such information will be applied knowledgably and ethically. [3] The question is where to draw the line between enhancement that is beneficial vs. the putative unknown harm associated with the intended improvement. (Another question is what happened to the time when dogs were valued most for their companionship and what really mattered was whether or not it was a “good dog”.)
While inbreeding of human beings for purposes of enhancement is not a consideration, the possibility that an individual could one day decide to genetically endow the embryo seems a plausible option in a market-driven environment lacking stringent regulatory guidelines. Cynics of the new genetic data may imagine parents choosing the genetic profile of their offspring: eye color, height, IQ, but real consideration is being given to the eradication of birth defects, disabilities, mental illness, any and all heritable diseases and their attendant societal burden. Why not then insert or delete a gene or two to make us all ultra-intelligent, disease resistant, living indefinitely with a retractable third arm – weightless of course? Too cynical you say? Exaggerating the possibilities without any insight into the reality of genetic medicine? We came of age in a world where the first test tube baby was born and life-saving organ transplants became commonplace. Today our children and grandchildren are learning that IVF is where babies come from and that in the face of overwhelming demand, scientists are attempting to grow organs for transplant in Petri dishes! Nothing has deterred us from cosmetic surgery, gastric bypass, liposuction, implants or transplants if they offered a better life and we could afford them, and that is the reality of our young people. What will motivate them to deny their children future beneficial offerings? Thoughts of genetic selection and enhancement may wake you up in a cold sweat, but in a market-driven economy where the seemingly bizarre and futuristic come to life with regularity and nothing seems impossible, they may not be as far-fetched as at first they seem. (Juxtapose this scenario with the sobering realization that while we deliberate over our children’s eye color, much of the world is denied basic medical care and you won’t get to sleep at all.)
But are we so simple to genetically manipulate and predict? Will we allow our science to continue to imitate our science fiction or will we begin to appreciate the limitations of science, the delicate balance of nature, and the power science offers us to destroy that balance?
Access to enhancement and selection of superficial physical characteristics, it can be presumed, will be limited enough to make them the very least of our concerns for now. (Guess that third arm will have to wait.) But eliminating disabilities and heritable disorders usually place high on the list of reasons given for pursuing genetic screening and intervention. Perhaps all of us good, rational people will agree on a modest list of genetic diseases that ought to be targeted for elimination. However, not all agree that an anencephalic newborn or a fertilized embryo held in reserve during treatments for infertility ought simply to be discarded; therefore it is likely that not everyone will agree on which genetic traits ought to be priorities for negative selection. The most likely candidates initially would be early onset, dominant conditions that cause unrelenting suffering and early death, but others such as mental illness, alcoholism and substance-use disorders with genetic underpinnings have also been suggested as targets in light of the medical burden they place on society. Clearly, the specific diseases and conditions we would vote to eradicate would vary according to our experience and our perspective, but that is just one of the many reasons we should carefully consider this course of action.
Science is an ever-expanding spiral of knowledge where new theories continually refine or replace long-held beliefs. The central dogma describing genetic information transfer from DNA to protein, once the keystone of molecular biology, is now believed to be an oversimplification as mounting evidence has revealed a much more complex scenario. Rather than one gene expressing one protein, most genes can be alternatively spliced to produce a number of proteins and each gene is regulated in a variety of ways so its expression can be precisely controlled. Identifying disease genes can be an arduous process even for Mendelian traits and in many cases our knowledge is still too limited to accurately predict the gene underlying a disease phenotype. [4] Many common diseases involve multiple mutations or gene interactions. Different mutations have been found to produce the same phenotype while the same mutation can result in phenotypically variable effects. Additionally, social and environmental factors frequently contribute to clinical variability of disease, at times even determining the probability of disease onset.
Genetic differences must exist between individuals in order for natural selection to result in evolutionary change. Artificial selection through genetic screening or intervention could eventually compromise our diversity and thus diminish our responsiveness to environmental challenges. Most genetic defects are autosomal recessive traits and natural selection is believed to maintain these mutant DNA sequences in populations. Different relative fitness levels of heterozygotes compared to either of the homozygotic genotypes in particular environments may suggest that genetic variation is maintained in populations for purposes related to survival. Seemingly defective genes can confer advantages we may only become aware of in particular circumstances. To rid the human gene pool of such mutant sequences could upset the fragile balance of which we remain largely unaware. The evolutionary advantage of increased resistance to malarial infection bestowed by the sickle cell trait is not likely to stand alone and comparable advantage may be imparted in many instances, although the intricacies of gene action have not yet been unraveled. The advantage for cystic fibrosis heterozygotes for instance is theorized to be resistance to dehydration effects of diarrhea and heterozygote advantage at HLA class I loci has been demonstrated for some infectious diseases such as hepatitis B and HIV. [5]
We are often mistaken in our perceptions and we are responsible for the deep human sorrow we cause. Our ignorance and fear prejudice us against that which is different and make us intolerant of it. For example, we have always had a difficult time understanding mental illness, so we may justify our decision to eliminate it altogether, citing severe and unrelenting suffering of the afflicted. By the same token, we may choose early intervention when we see that extra copy of chromosome 21 to eliminate even the chance of Down’s syndrome because the mere presence of that chromosome cannot tell us how mild or severe the retardation effects will be. We may choose to select against the embryo with any one of a thousand different mutations that can cause cystic fibrosis in the one allele, cystic fibrosis transmembrane regulator (CFTR) although, again, the precise form of the manifestation cannot be predicted. We may decide lives that will almost certainly be interrupted by late onset diseases like Huntington’s aren’t worth beginning. The haunting questions that arise: Who decides what quality of life is worth living? Who counts as a person? What constitutes societal burden and at what point does that outweigh personal autonomy?
That which is considered normal or acceptable by society’s judges is subject to interpretation and change. Temperaments or behaviors may be better tolerated within certain environments or at particular times, as is the case with bipolar individuals in artistic or literary circles where inherent creativity is paramount. [6] Additionally, not so very long ago, left-handedness was considered ‘wrong’ and children were forcibly taught to use the right hand. In today’s world, this is no longer an issue and either hand is acceptable. The same could be the case for other genetically-determined proclivities currently thought to be unacceptable and we must be sure when called upon, our judgment will not be clouded by prevailing viewpoints or historical context.
Mystery abounds in the realm of genetics and much remains beyond our comprehension. The example here is bipolar disorder, a devastating inherited disease that has long been linked to creativity yet a popular potential candidate for elimination through genetic screening once we can detect the genetic abnormality that predisposes individuals to the disorder. Multiple genes are believed to contribute to the variable manifestations of the disorder, in conjunction with environmental components, which can precipitate episodes of some phases of the disease. [7] Depressive phases may entail a significant amount of suffering for the most severely afflicted individuals – debilitating depression, suicidal melancholy, mercurial temperament, incendiary tempers and uncontrollable rage, while the manic phases are associated with heightened mental acuity, clarity, ebullience, creativity and phenomenal bursts of energy and productivity. [6] Alongside being fundamentally good people, bipolar individuals can be charismatic leaders and that quality has led evolutionary psychologists to suggest a role for them in the formation of early societies. Predicting which individuals would be severely affected by this complex disease on the basis of genotype is simply impossible. The overlap or even causal relationship between manic depressive illness and creative temperament prompts us to consider what other value hidden in the genetic storehouse of knowledge we may miss in our myopic pursuit of eliminating an incalculable risk of suffering.
Regulation or moral guidance in the use of existing technologies is sorely lacking, an unwise precedent for the biological age. Willing to deny use of surplus embryos for the creation of stem cells, ironically, the United States has no governmental regulations or legal oversight for IVF or PGD. Using embryos obtained by IVF, one of the cells of the three day embryo is removed for genetic testing, presumably for those traits that would cause unrelenting suffering for the offspring and its family. In the context of selecting embryos that are not carrying life-compromising genetic traits, it is not clear where the restraint lays, in the autonomy of the substitutive judgment of the parents, or by direction of a genetic counselor, insurance company as third party payer, or some combination of these agents. Absent answers on what the moral or ethical grounding is for making selective decisions about an embryo’s genetic qualities and hence implantation, PGD has been used in the United States to avoid births with “serious genetic defects” since 1990. [8] (It is still too soon to know if the selections made were able to fulfill the hopes of the moral agents.)
Examining Therapeutic Options
Without gaining consensus on which genetic traits ought to be eliminated, or just rooting for morality and compassion to win the day, perhaps the alternative path is to fix that which is impaired. It is the hallmark of biomedicine to explore the cause of disease and find a therapeutic solution. In principle, gene therapy should be applicable to the management or correction of many diseases for which effective treatment is lacking. But gene therapy has turned out to be somewhat more complex than anticipated, requiring interdisciplinary collaboration between many competent professionals in a wide range of fields. More than twenty years of research has resulted in only limited success [9] and more than a few unforeseen repercussions. Two readily come to mind: Failure to monitor toxicity levels of transgenic material and magnitude of host immune response to delivery vectors has resulted in patient death. [9] Successful treatment of infants with X-linked SCID in a retroviral gene therapy trial was followed only three years later by development of T cell leukemia in an unexpectedly high percentage of the patients as a result of insertional mutagenesis near a known oncogene (cancer-causing gene). [10] While lessons have been learned, remarkable advances have been made and extraordinary potential is still promised, the reality is that we continue to search for efficacious delivery vectors that can direct transferred genes to specific cell types or tissues and are still attempting to achieve and maintain appropriate expression levels for correction of specific disease phenotypes. Fulfillment of promises is years away even for disorders involving single defective genes.
In lieu of that, perhaps genetic research in pursuit of better treatment options would be the most viable alternative. If biomedicine can reach the gene level and distinguish between gene variants that confer disease risk or protection, both new and existing drugs or therapies could be more discriminately administered with potentially increased success rates. Additionally, the dawning era of pharmacogenomics heralds specifically designed pharmaceuticals particular for each individual’s genetic composition, thereby offering greater safety and efficacy than conventional therapies. Gene variants or alleles certainly exist within populations and an individual’s response to a particular treatment may vary accordingly, so personalized medicine sounds like an idea to be pursued, although the initial cost will likely be prohibitive for most. Alleles are even known to have different ethnic distributions and which alleles a population carries can influence their risk of acquiring the disease associated with their particular gene variant, so the appeal of race-specific drugs is growing as their potential to reach underserved populations is pitched. This despite the contention of scientists that there is no biological basis for the concept of race and the fact that very few drugs have actually demonstrated even the possibility of differential benefits among ethnic groups with regard to safety or efficacy. [11] Segregating medicine sets an inadvisable precedent and will not address the underlying causes of health care disparity.
Genetics is not Destiny
Before we get our hopes up over these new therapeutics, it is important to realize that except for single-gene diseases, the influence of most known genetic variations on disease susceptibility is relatively modest. [12] While the potential risk of disease may be indicated by the presence of particular gene variants, genetics is not destiny as many other genetic and environmental factors can interact to influence the ultimate outcome. There is a rather high P value on genetic diagnoses and the uncertainty associated with genetic information heightens the confusion for a public increasingly expected to decide for themselves how best to use that information.
In many ways more educated than ever and better able to make health care decisions independently, it is still unclear if personal genetic profiles will be digestible enough to be of use to the general public in identifying their potential susceptibilities and implementing any behavior modifications that could alleviate their risk of disease. It will be interesting to see the results of the study being conducted by the NHGRI to determine just that [12]; meanwhile, we are free to speculate. In an increasingly competitive medical marketplace, the public has been inundated with advertisements prompting them to question many aspects of their normalcy and then ask their doctor if yet another drug is right for them. It is fair to assume that those advertisements would not run for long if no one was asking. Individuals claim the right to make decisions regarding health care, willingly engage in self help and readily seek ways to diagnose themselves, which the market then eagerly provides. Consumer-direct marketing has resulted in everything from home pregnancy and HIV tests to websites such as DNA Direct offering genetic tests for breast, ovarian and colon cancer risk, diabetes and cystic fibrosis risk, infertility and drug metabolism disorders, among others (www.dnadirect.com), making it possible for any person with access to a computer and a credit card to determine their health status without consulting a doctor or other health professional. Such autonomy may be attractive to those who fear discrimination by an employer or insurance provider, but exposes inequities in health care access based on inability to pay as well as a dire need for oversight and regulation of the selling or overselling of these services and the consequences posed by misinterpretation of the results.
As genomic diagnoses mature and our susceptibility to more and more genetic disorders can be discerned or our response to particular drugs can be determined, it seems reasonable to assume that at least some people will be receptive and attempt to include the information in their decision-making processes concerning a course of treatment or lifestyle modification. Initially, this information will be requested on an individual basis and sought after some treatable health problem has surfaced. But eventually, it can be presumed, many of the tests will become a normal part of pre-natal or early childhood care and the decision on the part of the parents to ‘know’ or not may well be more dramatic than the one they face today concerning the gender of their fetus. Some disorders may not be preventable or curable while others may be nearly impossible to accurately predict on the basis of genotype alone. Will we be left to sort this out for ourselves as well? Will we want to know for ourselves, let alone our progeny? If for ourselves, and we can act, will we? If for our children, will society and insurance companies pressure us to act in a prescribed fashion? Fearing lawsuits, will physicians be forced to advise preemptive action based on genetic predisposition even for diseases we may never get? As the competitive market responds to the growing demand for these informational goods, who will offer assurance that the best interests of the consumer are being looked after?
A Role for Dialogue
Where mystery abounds, ignorance thrives. The novelty of genomic science and technologies is leading researchers to be aggressive in their attempt to learn as much as they can in a short period of time, and not without competitive motivations. We the people are only too ready to believe and base major life decisions on the claims of exuberant investigators and the media, whose enthusiasm has been known to lead to mistaken perceptions of the development and success of medical approaches. It is imperative that their sense of responsibility be enlisted in fully considering the consequences of the knowledge they impart to a public body anxious for treatment advances and possibly less than completely informed as a result of attempting to stay current through headlines and sound bites. First and foremost, information must be presented as realistically and as comprehensively as possible so the public can make informed choices about their lives.
An illustrative albeit unscientific case in point begins in the field of alcohol research, where investigators are all but trumpeting the news that they are making progress in identifying specific genes that may be related to the disease phenotype and claiming that through genetic counseling, at-risk individuals will soon be able to make informed choices about their lives. But alcoholism is a multifactorial disease believed to involve variations in many different genes and their modulating factors as well as a host of social and environmental influences. Several types of analyses have begun to converge on a number of regions on chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 13 and 16 that researchers believe may contain genes that could affect the risk for alcoholism either positively or negatively. [13] In addition, many environmental factors have been reported to contribute to the occurrence of disease including psychiatric comorbidity, exposure to high-risk environments such as alcoholic households or childhood sexual abuse, and a few studies have even identified apparent associations between risk for alcohol dependence and such factors as family religious background or place of residence. [14] While the literature states that the continued study of genetic and environmental interactions is important, the strongest suggestion is that the solution will be found in the genes and any environmental impact could only increase the risk for dependence. Most disconcerting is the statement that individuals who are both genetically and environmentally at high risk for alcoholism but remain unaffected “may carry genetic factors that help protect against the development of alcoholism”. [15] Undoubtedly some variants of implicated genes will be protective; nonetheless, it is clear that the nature of the studies done thus far (whole genome linkage analysis, family studies, electrophysiological measures) are biasing researchers to miss a very important group: those individuals who were both genetically and environmentally at high risk for alcoholism but remained unaffected not necessarily because of their genes but because of another environmental factor that positively influenced them, perhaps a friend or relative, a teacher or even a total stranger, a book, a movie, a dream: something that could pierce the darkness and make them aware that life could be different than what they knew. One of us (Hise) along with two younger siblings is descended from two long lines of alcoholics and was raised in a high-risk environment that included psychiatric comorbidity. But all three siblings, now squarely in their forties, remain unaffected although, typically, each took a turn on the dance floor with alcohol in their youth. While they may be something of a statistical anomaly, when asked the reason they believe they didn’t succumb to alcoholism, each would credit the echoes of their maternal grandmother resounding in their ears, repeatedly reminding them of the perils of alcohol and impelling them not to be like the rest of the family. Consequently, they were able to make better choices than those before them, without ever consulting their genetic report card. The power of positive influences in our lives should never be discounted. But here, where investigators primarily intend to make a case for their research, no mention is made of anything like that to present a complete picture to the interested public, even in publications expressly dedicated to the education of the layman. Until the science is a bit more definitive than shown in these studies, the omission deserves at least to be noted.
The scientific community has virtually convinced the public that genes are deterministic and with time they will enable us to manage if not prevent even complex, multifactorial diseases. The reality is that the presence of susceptibility genes in itself does not necessarily indicate eventual disease manifestation, and even if it did, we cannot control every aspect of our lives to prevent those diseases. But to have value, life does not have to be perfect or everlasting; in fact we learn more from it if it isn’t.
As potentially helpful as genetic testing may be to individuals who have access and choose to use the information, genetic testing is not likely to be universally available. Like expensive therapeutic drugs and treatment for infectious diseases, genetic medicine may serve only those whose birth lottery places them in a position of privilege. The ideal embraced in the human rights movement rests on the cardinal axiom that all human beings are born free and equal, in dignity and rights, and are endowed with reason and conscience. The Declaration of Human Rights crafted in 1948 calls forth an ideal of human community – an ideal far from our shared reality. The U.S. did not ratify the declaration until after the civil rights were separated from economic and political rights in 1992. Subsequently we ratified the civil rights portion leaving the economic package untouched. Given this history and the grounding of the Declaration of the Human Genome UNESCO document in human rights, it is reasonable to be concerned about fair and universal access to genetic applied knowledge for all persons of “equal dignity of respect.” Dialogue and oversight can provide guidance to help us all keep the promises of science in perspective, to enable us to understand that genomic research is still in its infancy and allow us to imagine novel ways of realizing collective benefits through fair, ethical distribution.
Conclusion
Louis, the trumpeter swan settled into life with his mate and their cygnets after restoring the honor of his father. “As he relaxed and prepared for sleep, all his thoughts were of how lucky he was to inhabit such a beautiful earth, how lucky he had been to solve his problems with music, and how pleasant it was to look forward to another night of sleep and another day tomorrow, and the fresh morning, and the light that returns with the day.” [1, p 210] Gratitude for life does not depend on perfection but on a value for the gift.
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