Patricia had missed her first two appointments at the Genetics Center, but her dad assured us she’d be there this time. We scheduled her as our last patient of the day—just in case she’d be a no-show again. She had been referred by her family physician, who believed she might be manifesting early signs of Huntington’s disease (HD), a neurodegenerative disorder that is incurable and always fatal.
HD is inherited as a dominant genetic disorder—a single gene passed from either parent will result in the development of this disorder. But those who inherit this gene rarely show any visible symptoms before reaching middle age. In fact, typically about 50 percent of those who inherit this gene will be free of any discernible neurological impairment until their fifth or sixth decade of life. Although representative of a group of genetic conditions known as late-age-of-onset disorders, HD—once initiated—culminates over the next 15 or 20 years in ever-increasing debilitation, dementia and ultimately death. It certainly isn’t surprising that individuals diagnosed with HD commit suicide at a very high rate.
Until the past decade, the diagnosis of the onset of HD was based solely upon neurological examinations. The accuracy of such diagnoses varied markedly when focusing upon patients in the earliest stages of the disease. However, this situation changed dramatically when the tools of molecular genetics, developed in concert with the Human Genome Project, could definitively identify the HD gene.
Pat, a 38-year-old single mother, did make her scheduled appointment. She was joined by her father, Pete, and her two daughters, Pearl, 9, and Paula, 12. The girls each had different biological fathers, who were no longer involved with the family. We reviewed Pat’s medical and family history carefully, including the neurological report of her family physician.
The previous Christmas Pat’s mother had died at age 68 of HD, almost 16 years after she had been first diagnosed. Observing a family member suffering from the relentless progression of this disease had had a profound and agonizing effect upon all members of Pat’s immediate family. Clearly Pat was quite knowledgeable about HD and was both convinced of her diagnosis and totally resigned to the devastating fate of developing HD. “I saw what happened to my mother,” she told me. “I know it’ll happen to me just the same.”
Pat was adamant that she did not wish to undergo genetic testing. “I just don’t need to know if the test says I’ve got it,” she said. “I need to keep my job, and I need to have my medical insurance, too.” I assured Pat that the results of the testing would be totally confidential—guaranteed so by federal and state regulations. What I didn’t expect was her next comment. “But the girls need to know—I want the girls to know. I want Pearl and Paula to be tested right now!”
Because of the potential impact of this knowledge on a youngster’s life, geneticists are reluctant to provide HD testing for minors unless there is a compelling medical reason, such as specific neurological symptoms in the child. Pat insisted, arguing that she was hoping her sister would consider adopting Pearl and Paula but knew her sister would do so only if they did not possess the HD gene. “She won’t take ’em if they have it,” she said, and she wanted to have the girls tested so she could plan for their future while she was still competent to do so.
I struck a deal with Pat. “Let’s test you for the HD gene with the DNA test that’s now available,” I suggested. “If you’re confirmed ‘positive,’ we’ll then consider all the reasons why you should or should not go forward with the testing of the girls.” With considerable reluctance, she agreed. A blood sample was obtained and shipped off to the diagnostic laboratory.
Prior research had shown that the HD gene is part of a class of genetic disorders known as “expanded repeats.” In other words, the DNA molecule of the HD mutation was found to be lengthened, in comparison with the normal counterpart of the HD gene, by having extra bases (steps) at one end of the DNA double helix. By ascertaining the pattern and number of such “repeats” of the HD gene in individuals at any age before or after birth, highly accurate confirmation of the condition can be established (even though such individuals may remain totally non-symptomatic for several subsequent decades). So the lab was looking for such “repeats” in the DNA of Pat’s blood.
Six weeks later Pat returned to the clinic, and we shared the results. The DNA test showed that the number of expanded repeats in the region of the HD gene was well within the range of a “normal” individual. She was not a carrier of the HD gene. And I was off the hook about testing Pearl and Paula.
Now I look forward to receiving the annual photo from Pat and the girls each Christmas. The girls are in high school and doing nicely, and Pat is an avid motorcyclist.
Arguably, the three most significant biological landmarks of the past 150 years are Darwin’s articulation of the theory of evolution (1859), the modeling of the structure of DNA (1953) and the culmination of the Human Genome Project (HGP) with the elucidation of the chemical sequence of the human genome (2001). Indeed, the significance of the first draft by the HGP has been so far-reaching that it has been referred to as the Holy Grail of genetics. We have since been deluged by streams of magazine and newspaper articles heralding a new era of medical advances. It is suggested that the knowledge gleaned from the HGP will most certainly reshape biomedicine and, in the rosiest speculation, will mark the beginning of the end of human disease—either through the substitution of a normal gene for one that was defective (gene therapy) or by the alteration of a missing or flawed gene product critical for normal development or proper metabolism.
Not surprisingly, a whole new industry, predicated upon the fervent belief in engineering better living through genetics has developed—an industry directed and thus legitimized in great part by the very scientists whose studies in the nature and structure of DNA made all this possible. Medical practice is already benefiting from new and more powerful diagnostic tools drawing on the knowledge provided by the HGP. Newborns are now being screened for an ever-enlarging spectrum of possible genetic disorders, ranging from relatively common conditions such as sickle cell disease and cystic fibrosis to rare metabolic flaws. These early diagnoses, often prior to the development of any symptoms, are providing the opportunity for early therapeutic interventions and, in many instances, markedly improved outcomes.
We are likely to achieve the capacity to fully recognize genetically conditioned health risks within a decade. However, the capacity to directly replace “aberrant” genes (gene therapy) will require a significantly longer period of time. Francis Collins, director of the National Human Genome Research Institute, rather optimistically estimates that “by 2010 screening tests will enable anyone to gauge his or her unique health risks, down to the body’s tolerance for cigarettes and cheeseburgers, and by 2050 many potential diseases will be cured at the molecular level before they arise.”
Whatever the exact time period, society is in a unique position now, before the full implementations of these powerful technologies are upon us, to consider some of their awesome potentials. We are at the threshold of one of the most significant technologies ever developed and have been accorded the opportunity to reflect upon some of the significant social and personal implications of the new genetic technology before its full actual implementation.
As science journalist Matt Ridley explained, “I began to think about the human genome as a sort of autobiography—a record, written in ‘genetish,’ of all the vicissitudes and inventions that had characterized the history of our species and its ancestors since the very dawn of life. . . . In just a few short years we will have moved from knowing almost nothing about our genes to knowing everything. . . . We stand on the brink of great new answers but, even more, of great new questions.”
Some of those questions: How can and how should individuals and society respond to these advances? Who will most benefit from such developments? Is it likely that individuals with risks for developing such abnormal physical or mental conditions as Lou Gehrig’s disease, breast cancer, dyslexia, schizophrenia or attention-deficit disorder will be identified and thus constitute a genetic “underclass”? Could genetic discrimination become a common reality? As with any societal resource, decisions must be made. Who will and who should determine how such technology is allocated? And, of even greater concern, what will be the benefits, drawbacks and “costs” to society’s values and beliefs?
Understanding science is a prerequisite for dealing with these challenging societal implications, and that understanding begins with DNA. DNA is the genetic material. The image of the double helix, the structure of this molecule with its paired chains and cross “steps,” is widely known through its representation in print, popular films and video clips. What’s less well known is that each step on the twisting ladder of the double helix is a pair of chemical bases. Only four types of such bases exist in the DNA molecule. Amazingly, all the information required for the full development of an individual is encoded within those base pairs or steps. As a result of the completion of the Human Genome Project, virtually each of the three billion steps of our DNA molecules has been identified and logged. A full listing is readily available to anyone on the NIH website www.ncbi.nlm.nih.gov. That, in short, is the product of the HGP.
The gene is the fundamental unit of inheritance. It is presently believed that there are 20,000 to 25,000 genes in our genomes varying in size from several hundred to several thousand steps. Thus, each of our 46 chromosomes contains a single, long (one yard) DNA molecule. A complete chromosome set is found compacted into each microscopic nucleus of virtually every one of the 100 trillion cells of our body. A fertilized egg contains half (23 chromosomes) of its genetic endowment from the mother’s egg and half (23 chromosomes) from the father’s sperm.
The term genome refers to the genetic constitution of the egg or sperm. Thus we possess two genomes in each of our cells. All of the information required for the development of an individual is provided by these two genomes. An enormous pool of integrated information is encoded within the DNA packaged in our 46 chromosomes.
It may be useful to envision the genome as a 23-volume encyclopedia set containing all of the composite data required for the construction of a human being, with each individual chromosome representing a different volume comprised of several thousand entries (genes), each with specific structural and/or behavioral instructions.
We now believe that there are about 25,000 entries (genes) in the human genome with the specific “wording” of these entries crafted with a simple but clever four-letter alphabet formed by the bases or steps of the DNA molecule. All living organisms use the same alphabet and share a common, universal code to specify developmental (constructional) operations. Thus, all the information required to direct the development of an individual is contained in the fertilized egg.
We also now possess at least some information regarding half of our genes, and the pool of information grows on a daily basis.
The Human Genome Project was designed to allow us to identify our genes and to provide fundamental information regarding their function. This represents a vast contribution to so-called “pure” or basic science. But it’s important to understand that the justification for investment of the enormous resources to support the HGP was an implicit promise of its potential benefit to human health. In great measure, the primary goal has been achieved. We are close to identifying all of our genes and their functions. In turn, that has opened the way for the screening and detection of a growing list of genetic diseases. Today, cystic fibrosis, sickle cell disease, Fragile-X syndrome, Duchenne muscular dystrophy, thalassemia and Tay-Sachs disease are but a small sample of the genetic conditions that can readily be confirmed in an individual well before birth.
Even though therapeutic interventions are not yet possible for most of these diseases, this is a necessary first step. At this time, information gained from the early diagnosis of an affected fetus can provide the parents the opportunity to prepare medically and emotionally for the management of a newborn with such a condition. Tomorrow, it’s hoped and expected that therapeutic intervention will be available to “correct” the abnormal gene—either by controlling its aberrant function or by replacing it with a normal gene.
To predict the direction of future genetic researches, it’s also important to remember now the history of the HGP project itself. Initially, in 1990, the HGP was conceived as a private, federal and internationally funded consortium intended to provide freely shared results. However, significant pressure from private industry made the program a “race” and then a dual effort, both publicly and privately funded, to accelerate the pace of the project. The first “draft” of the Human Genome sequence was reported jointly in 2001, as was the more complete compendium that followed in 2003. Thus was born the new field of _genomics_—the study of information flow within cells and tissues, with primary focus upon the organization, function and evolution of our genetic endowment. Worldwide research activity in both public and private arenas has been so intense and the flow of information so immense that a whole new field of bioinformatics has emerged, armed with sophisticated computer technologies with the primary mission to “crunch” and decipher the huge bodies of genomic-generated information.
Without question, both the public and, perhaps even more aggressively, the private sector will determine the future directions of genomic researches and, in particular, their applications for human health. But market forces are likely to play as important a role as science in those outcomes and the future applications. The HGP has already spurred wonderful medical advances being implemented in the private sector. The most obvious advance at this stage has been the enhancement of our diagnostic capacities and abilities to identify numerous genetic disorders, creating new diagnostic service providers.
However, special clinical, social and ethical issues have also arisen. Some are obvious. For example, information about an individual’s genetic makeup of this nature inevitably raises concern about privacy. To whom does “genomic” information belong? Should data regarding your genetic health be shared with other members of your family or with your community at large? Does this information belong to the insurance carrier who may have paid for the testing? What about your employer? Could information related to an elevated risk of a future medical condition adversely affect consideration for a possible promotion or even result in your dismissal? Will it compromise future insurability?
Today we are moving toward the creation of a national identity card. It doesn’t take much imagination to envision a truly comprehensive identity card that would not only have your photo and establish your residency but also would include a CD containing your very own DNA sequence. This would at once establish your sole identity, be difficult if not impossible to counterfeit and, simultaneously, would be immensely useful in a medical emergency. But giving others such access to your own personal genetic information certainly raises concerns well beyond privacy.
For example, what if Pat had been diagnosed with HD? Should her young daughters be tested? If Pat’s test had shown the presence of the HD gene, would it be wise, or humane, to share those results with the girls or their extended families, given the dire prognosis? Because HD is also a very late-acting gene, should testing of family members of an HD patient be undertaken when no effective preventive measures can be offered?
Certainly, there are positive values in obtaining genetic information. But such knowledge may likely influence personal procreative decisions. Once we have bitten into the apple of genetic knowledge, we may face issues of choice we never had to confront before. Are we prepared to enter an era where genetic information not only can but should be assayed, evaluated and incorporated in marital choices and family planning?
Current testing for Tay-Sachs disease—a fatal wasting neurological genetic condition that results in the death of an affected child by age 3 or 4—has influenced such decisions by members of high-risk populations. The abnormal gene responsible for Tay-Sachs disease is found in all populations but in differing frequencies. The incidence in the Ashkenazic Jewish population is tenfold that of the population at large. Among orthodox Jewry, adolescents are required to undergo testing to ascertain if they carry a single copy of this recessive gene. Two copies are necessary to produce the disease; thus a couple who are both gene carriers are at a 25 percent risk of bearing an affected child. For some couples this is an excessive risk, for others it may not be. Nevertheless, Orthodox Jewish rabbis strongly discourage and may even deny the sanctioning of marriage to a couple who are both carriers of the Tay-Sachs gene.
The results have been impressive—over the past decade the birth of Tay-Sachs-affected children in this population has virtually been eliminated. Is it unethical or possibly even immoral _not _ to use genetic information in family planning when we know that such information exists?
Indeed, thanks to a better climate of public awareness, we know that a good prenatal environment is critical for the development of the child. We urge concern for proper maternal diet and the need to provide the fetus with a “smoke-, alcohol- and drug-free environment.” But what about prenatal or pre-prenatal genetic concerns? Aren’t we also obligated to provide society’s children the best possible genetic endowment? As the fruits of the HGP ripen, allowing us to be ever more knowledgeable about genetic contributions to our health and development, aren’t we and our health providers obligated to ensure the best possible hereditary endowment, too? How so? Do we possess sanction to bear children without concern about their future health and the welfare of future generations? Shifting the focus, do our progeny have the right to be born with a “sound mind and body” if possible?
What about society in general? What is society’s role in procreative issues? Since society is often called upon to support individuals with special needs, should it play a more dominant role in mandating widespread genetic education? But who is “society”? Certainly all of us have a significant stake in addressing the tough decisions the new genetics will present—the professionals and nonprofessionals, the young and the old, doctors and patients, the genetically informed and uninformed, our policy makers and policy “breakers,” those with special and specific agendas. The recent history of the Terri Schiavo case provides a vivid example of disparate societal values and competing family, political and public interests. In turn, this suggests that society is a multifaceted animal and that coming to consensus or plan of action will be a significant challenge.
The HGP has markedly accelerated the development of strategies for the treatment of genetic disease. Gene therapy, the actual replacement of malfunctioning genes, is in the early stages of development. Although we currently possess limited capacity to directly correct or replace an abnormal gene, we are ever more able to circumvent the ravages of genetic disease at steps away from the mutant gene, through dietary control or by providing the missing gene or replacing an aberrant gene-controlled product. Such intervention has proven highly effective for the treatment of a growing number of genetic conditions including PKU (phenylketonuria), and Factor VIII replacement in hemophilia A.
Yet these and other treatment strategies possess potential consequences. Most notably, are we possibly polluting the human gene pool by increasing survival rates of carriers of genetic disease by treating and “curing” them before birth?
We will need to revisit the concept of disease itself, and what we mean by and define as “normalcy.” Most of us would agree that many serious and life-threatening genetic diseases are “abnormal.” But what about those traits with significant genetic components that don’t directly equate with disease? Traits like physical appearance, height, behavioral and emotional characteristics, and cognition all have genetic components as well as environmental ones. In the near future, we are likely to have the capacity to choose those traits for our children, to move “nature” closer to “nurture”. Indeed, the current controversies involving performance-enhancing drugs will seem insignificant in comparison to one focused upon performance-enhancing genes. Who is and who should be making those decisions? Are we, as individuals and as members of society, informed, willing and able to determine how to properly support the “abnormal” or “exceptional” and to decide what genetic interventions are both desirable and appropriate?
Where does all this take us? Indeed, despite these awesome challenges, I’m optimistic. Although our present-day predictive capability markedly outstrips our capacity to prevent or treat genetic illness, this gap between the potential and the reality gives us time to ponder these questions at length and depth. We should rejoice that human suffering can be alleviated by this knowledge. But we also will be challenged—and perhaps are already being challenged—to develop and provide new support services to fulfill the promise offered by the Human Genome Project. That calls for a new, shared vision of the society we want to become.
We will need a new social policy not made in a laboratory or by executive order but by an informed, free democratic society. As members of such a society, it is our privilege and responsibility to prepare for a braver new world than Huxley ever imagined.
Harvey Bender is a professor of biological sciences and director of the Human Genetics Program at Notre Dame. He has directed genetics centers at South Bend, Indiana, hospitals since 1979 and also serves as an adjunct professor of medical genetics at the Indiana University School of Medicine.