The natural trajectory of human genome research is toward the identification of genes, genes that control normal biological functions and genes that create genetic disease or interact with other genes to precipitate hereditary disorders. Genes are being localized far more rapidly than treatments are being developed for the afflictions they cause, and the human genome project will accelerate this trend. The acquisition of genetic knowledge is, in short, outpacing the accumulation of therapeutic power -- a condition that poses special difficulties for genetic knowing.

Our expectation is that the characterization of a disease- instigating gene will greatly assist our understanding of how and why it causes a malfunction in the body. It makes good sense to go to the root of the problem. But to learn a gene's secret, first you must find it. And finding it is not so simple. It is much easier to locate the neighborhood in the genome where a gene resides than it is to determine its exact address.

Genetic jackpot.

At Massachusetts General Hospital, DNA was extracted from blood samples from the Venezuelan family members. Jim Gusella was also studying a large American family with Huntington's disease from Iowa. He searched the DNA from these two families for a telltale marker, helping to develop what were to become standard laboratory procedures in such ventures. Jim sliced up each person's DNA with restriction enzymes. He then developed markers, RFLPs, which he made radioactive. These markers were called anonymous because he did not know on which human chromosome they were located, only that they were in one unique spot in the genome, just like a gene, and they came in several forms so that individuals could be differentiated from one another. The fragments of chopped-up DNA from the family members were put on a gel that separates fragments on the basis of size. The radioactive probe (denatured, or single- stranded) was then added. When the probe is radioactive, it would "light up" where it was stuck on the gel, revealing distinctive bands. One would then need to check if a certain pattern of bands appeared only in individuals who had the disease and another pattern in their relatives who were healthy. If this difference was true more often than would be expected by chance, it would be very likely that the marker and the gene were close together on the same chromosome.

We all expected that the detection of a marker linked to the Huntington's disease gene would require thousands of tests and probes, but the third probe that Gusella characterized and the twelfth one he tried hit the jackpot. He began with the Iowan family, whose samples were the first to be collected, and the probe, called G8, was weakly positive, but not significantly so.

This finding gave him the crucial push, however, to try G8 in the Venezuelan family -- and it was the only probe he needed! It immediately showed odds far better than 1,000 to 1 that it was very close to the HD gene. P. Michael Conneally at Indiana University performed the computer linkage analyses that definitely proved that this probe and the HD gene were close neighbors. Almost all the Venezuelan family members with HD had one form of the marker while their healthy relative had another. At the time linkage was discovered, the chromosomal location of the probe was unknown, but it was quickly mapped, using in situ hybridization and other techniques, to chromosome 4. By inference, the position of the gene was mapped as well. Out of 3 billion possible base pairs on 23 chromosomes, we now knew we were a mere 4 million base pairs below the culprit gene way on the very top of the short arm of chromosome 4. We triumphantly announced the feat in an article in Nature, in November 1983.1

It had taken us just three years -- an astonishingly short time -- to localize the HD gene. Our critics and even our supporters said, rightly, that we had been incredibly lucky. It was as though, without the map of the United States, we had looked for the killer by chance in Red Lodge, Montana, and found the neighborhood where he was living.

An elusive prey.

Next we needed to find the exact location of the HD gene, isolate it, and learn its secret. Since January 1984, the Hereditary Disease Foundation has supported a formal collaboration of seven scientists around the country and the world searching for this gene: Francis Collins, at the University of Michigan; Anna Maria Frischauf and Hans Lehrach of Imperial Cancer Research Fund, London; Peter S. Harper, University of Wales College of Medicine; David Housman, Massachusetts Institute of Technology; James Gusella, Massachusetts General Hospital/Harvard Medical School; and John Wasmuth, University of California, Irvine. The task has been arduous in the extreme in this inhospitable terrain at the top of chromosome 4. It has been like crawling up Mt. Everest over the past eight years. First we thought the gene was at the telomere, the very end of the chromosome. Now recent work has indicated that we probably jumped over the gene in our rush to get to the top and it actually is not quite to the end. I used to say confidently that we would be right on it within six months for sure, but I don't say that anymore.

Homozygotes for Huntington's.

I mentioned earlier that our first research interest in the Venezuelan kindred was to find a homozygote for the illness. Once a marker for the gene was found, we immediately used it to learn which offspring might have inherited the HD gene from both affected parents. This included the family which originally drew us to Venezuela, a family of fourteen children and more than seventy grandchildren and great-grandchildren. Over the last decade of work, we have also found two other families in which both parents have Huntington's disease and many more in which both are at risk or one affected, the other at risk. Eight probable homozygotes have been identified from these families and more undoubtedly exist.

Even though a dominate gene is defined as "dominating" its normal partner, the few homozygotes who have been found for human dominant genetic diseases have been described as more severely affected than heterozygotes for that same illness. This would suggest a dose effect, even for dominant disorders. The normal gene plays an ameliorative role, even in one dose, and two doses of the defective gene makes the illness worse.

Huntington's disease provides the only exception to this clinical experience: it is the first completely dominant human hereditary disorder that has been genetically documented. Those who are most likely homozygous are not different clinically from their heterozygote relatives. Some putative homozygotes are symptomatically normal, presumably too young yet to develop signs, others have minor neurologic abnormalities, while some have definitive Huntington's disease but no earlier or more severely than anyone else. One tragedy that homozygotes face uniquely: all of their children will be afflicted with HD, as the homozygous parent has no normal genes at the locus to contribute. This is especially agonizing in Venezuela, where the family sizes are so large. The cells of the homozygotes may hold clues that will unlock this devastating disorder but until an intervention is found their families barely sustain themselves in widening pools of suffering. Every year we examine more family members and every year our hearts sink. ...

In this work, it is, of course, imperative to get clinical diagnoses right, because if they are wrong, the genetic analyses are going to be totally incorrect. We are fortunate to be able to maintain contact with the family and return every year. A member of our team, a superb Venezuelan physician named Dra. Margot de Young, attends the family members year round. We try, as much as possible, to collect blood samples from an individual only once. But sometimes you find someone in whom a critical recombination event has taken place that can help localize the HD gene more precisely. It is essential to be able to return to that person to reconfirm the diagnosis and reanalyze a new DNA sample to eliminate the possibility of a laboratory error. Our continuing access to family members makes this reference collection additionally valuable; investigators specified that they would not recontact individuals who have contributed to other major family collections for genetic reference mapping and are thereby precluded from gathering clinical information or checking mistakes.

A new era: Prediction outstrips prevention.

While the search for the Huntington's disease gene goes on, painstakingly, the discovery of markers linked to the gene has opened a new, exciting yet troubling era: presymptomatic and prenatal diagnosis of Huntington's disease with no cure in sight.

Immediately after localizing the Huntington's disease gene, we confronted the question of genetic heterogeneity: Is the HD gene in the same chromosomal locale in all families with Huntington's disease throughout the world? Many other genetic disorders manifest genetic heterogeneity -- the causative gene may be on several different chromosomes, even though phenotypically the symptoms of the illness appear to be the same in all the affected families. Was our chromosome 4 home for Huntington's disease unique to the Lake Maracaibo kindred and an Iowan family, or was it universal? Over one hundred families have been tested from throughout the world -- in Europe, North and South America, even Paupa, New Guinea -- and in all of them the HD gene is in the same chromosomal locale on the top of chromosome 4. The actual mutations at that spot may turn out to differ, but the region is the same. Given its universality, we can now use G8 and other markers subsequently found closer to the gene to test whether an individual has the HD gene before any symptoms appear, even before birth. So here we confront our worst fears: our scientific success puts us on the threshold of an era of unknown but imaginable dangers. We can predict the flood but cannot leave or stop the tide. We can tell people that they possess the gene and will eventually come down with the disease, but we have no cure or even therapy to offer to soften the blow.

Cystic fibrosis as a model.

Whether or not a disease shows chromosomal heterogeneity (more than one chromosomal location), or allelic heterogeneity (more than one mutation in the same gene at the same chromosomal locus), makes a big difference in genetic counseling. A current case in point is cystic fibrosis (CF), the most common hereditary disorder of Caucasians. Those who suffer from it have pancreatic enzyme insufficiencies and severe lung abnormalities; they cannot clear fluids from their lungs, which become inviting parks for bacteria. Children with cystic fibrosis now often survive until early adulthood, but the disease eventually proves fatal. About one in twenty-five Caucasians carries a single abnormal gene for this condition but is not clinically affected. CF is a recessive illness; each child of two parents who both have one gene for the disorder has a one in four chance of inheriting two genes for cystic fibrosis and expressing the disease. There are about 30,000 individuals with CF in the United States. For a Caucasian person in the population with no family history of the illness, the likelihood of having a child affected is about one in two thousand. If a reliable test were available to detect carriers, people might choose to use it.

In September 1989, Francis Collins, Lap-Chee Tsui, and Jack Riordan isolated a mutation that is found in 70 percent of all individuals with cystic fibrosis.2 Screening people for this particular three-base-pair deletion known as delta 508 would identify 70 percent of all CF carriers. If, however, you test positive but your husband does not, you still will not know whether he really is negative or just has a different mutation, one of the remaining 30 percent not yet known. Calculations indicate that screening couples who are both CF carriers would detect one partner but not the other in more than half the cases. To put the matter another way, if you assume that because your husband or wife has tested negative he or she is free of the gene for cystic fibrosis, half the time you would be wrong. Eminent geneticists on behalf of the American Society of Human Genetics issued a statement, with which other experts convened by the National Center for Human Genome Research, the National Institutes of Health (NIH), the Department of Energy (DOE) Human Genome Program, and other Institutes of the NIH concurred, recommending against population screening for cystic fibrosis until additional mutations were found and the test was more accurate.3 Although testing could be beneficial for those with a known family history of CF, geneticists stated that any other testing was premature and certainly not the standard of care. They advised that widespread use of the test should await two essential elements: identification of a larger proportion of all mutations, and putting in place the service infrastructure to give the test with adequate counseling provided. (Over 100 new mutations have been found since 1989, and the requirement for a higher degree of accuracy of detection is being met. Adequate counseling services are still insufficient, however, and providing these may be even more difficult to implement than achieving the scientific goals.)

Genetic illiteracy.

In all of these screening programs people must understand the difference between being a carrier of one abnormal gene for a recessive condition, in which the carrier usually has no symptoms, as opposed to an affected individual who has two copies of the abnormal gene. People must equally understand that carriers for a dominant disorder, a late-onset illness such as Huntington's disease or polycystic kidney disease, will, in fact, get sick. In recessive diseases the carrier will become a patient. How do we explain technically complex and emotionally charged information to ordinary people, many of whom never heard of DNA and barely of genes, who have hardly a clue about probability, and whose science education never equipped them to make choices regarding these matters? How do we ensure justice in access to counseling services and make them available to more than the white middle and upper classes who typically utilize them now? Genetic diseases cross ethnic and class boundaries, but access to services, unfortunately, does not.

How do we guarantee that the doctors who test individuals or populations provide adequate genetic counseling when doctors themselves have minimal training in genetics and often fundamentally misunderstand its principles? What should we do about doctors who say to a couple with one child affected by cystic fibrosis and who are contemplating having another, "Don't worry, lightning never strikes twice in the same place." Or -- the ultimate in confusion about a genetically dominant disease -- "Don't worry about Huntington's, just tell 'em to marry out into families that don't have it!" Such medical mistakes have increasingly been addressed through malpractice suits, including wrongful birth and wrongful life cases. In wrongful birth cases, parents of a seriously impaired child bring an action claiming that the child should never have been born. The parents argue that they were deprived through the negligence of a health care provider of the information that they needed to decide whether to initiate or continue a pregnancy. Had they known, they claim, they never would have had the child. Wrongful life is an action brought by the child claiming that it should never have been born.4 Must we resort to the threat of lawsuits to ensure that good medical practices will be followed? Or should we have sufficient ingenuity and imagination to be able to introduce new genetic findings into medical practice without increasing the litigiousness of our already embattled society? I believe we can figure out how to offer people genetic information in a way they can understand and assimilate. We can resolve these difficulties if we start working on them now, before the deluge of new tests the human genome program will bring.

All in the family.

A major problem in presymptomatic and prenatal testing using linked DNA markers is that the whole family must be involved. When we have the gene in hand and can detect directly the specific mutation in the gene, we will only need to look at an individual's DNA. But for tests using linked RFLP's, the marker patterns of all the relatives must be traced to determine which patterns of the marker in that family is consistently traveling with the appearance of the HD gene. For example, in the Venezuelan family it is the C variant of the marker G8 that tracks with the HD gene, but in the Iowan family it is the A variant. Over time, the process of recombination will gradually change which particular pattern of a marker is near a gene, unless the marker is exceedingly close to the gene. If a gene and a marker are such close neighbors that they are virtually never separated, they are described as being in "linkage disequilibrium." Within a family, however, the same pattern of the marker will tend to travel with the gene and the few recombination events -- the random exchange of segments between two homologous chromosomes -- that may have taken place tend to be obvious. This is why diagnostic testing using linked markers must be done in families: it is imperative to determine what pattern of markers prognosticates HD in that particular family. It is a tedious way of doing diagnostic testing, but until the gene itself can be found it is the only way of doing it and it is how tests must be carried out right now, not only for Huntington's disease but also for polycystic kidney disease and others. (Anybody in a family with a genetic disease -- this probably includes everybody -- should think about storing samples of DNA from relatives whose genotype would be essential to know for diagnostic testing. This can easily be done by freezing a DNA sample extracted from blood. DNA can also be taken from the brain, skin fibroblasts, or almost any other tissue, even after it has been frozen for a long time. The most important relatives to you are those in the family with the illness and those clearly unaffected, parents of these individuals and your own parents. If you have a genetic disorder, banking your own DNA could be critical to your descendants. Each family might have its own genetic variation, its own "genetic fingerprint" of the gene in question, and it is best to preserve a sample of the particular gene that plagues your family rather than extrapolate from the genes from other families.)

There are many families in which an insufficient number of genetically informative people are living (or have banked DNA samples) to permit diagnostic testing for Huntington's disease. And many people would prefer not to know their own genetic status -- whether or not they will develop HD. Can anything be offered for these people? One kind of test -- called a nondisclosing prenatal test -- allows couples at risk to gather some information about a fetus. This test can tell, almost definitively, if a fetus is not going to have HD but cannot tell definitely if the fetus is carrying the gene.  ...

When we first began offering testing for HD, many of us involved in providing the test thought that nondisclosing prenatal tests would be a preferred option. It offers a chance to ensure that children would be free of the disease while at the same time protecting individuals at risk from learning potentially traumatic information. But comparatively few have utilized the test. Its worst aspect is the possibility of aborting a fetus with a 50 percent probability of not having Huntington's disease, the same risk as the at-risk parent. Just imagine -- you're pregnant or you've fathered a baby, you're attached emotionally, your fantasies are engaged, and now you're confronted with the choice of aborting a baby who might be perfectly normal. How easy will it be for you to become pregnant again? How fast is your biological clock ticking? What if it happens again? A one in two chance is high. Some people feel that aborting a fetus with a 50 percent risk of HD is equivalent to aborting themselves, a rejection of who they are and of their legitimate place in the world. This sentiment is sometimes voiced by those who are disabled, those who object to genetic testing on the grounds that it is designed to eliminate people like them. Because of these particular difficulties, nondisclosing prenatal testing must be offered in a context of intensive counseling and support. If the couple is willing and interested, it is extremely valuable for research purposes to study any tissues resulting from terminations, particularly with respect to learning more about the timing of the HD gene expression. It is possible that the gene is expressed only in utero.

Considerations for genetic counseling.

There are many factors that influence the nature and quality of genetic services. An important problem is timing -- when should you give genetic information? For a late-onset disorder like Huntington's disease, timing issues are complex. We are often faced with providing presymptomatic test information to someone whose affected parent is in the last stages of the disease or has just died of it. Etched in their mind's eye is the disease at its devastating worst. And now you are telling someone who is perfectly healthy and normal, "You have a 96 percent probability of having the HD gene" -- which they hear as, "You are going to be just like your mother or father." Wrenching news. ...

My fear is that when presymptomatic and prenatal laboratory tests become more rapid and accurate -- for example, when polymerase chain reaction (PCR) techniques can detect the mutation itself -- there will be a temptation to short- circuit the testing process, to make it faster and offer less counseling. But no matter whether the test is easy or not, the impact of the information is equally crucial for one's life. There is still no interdiction we can offer, no treatment or preventive. And even if testing can be done on a single individual without DNA samples from relatives, Huntington's disease is a family disease and the test results for one member reverberate through all.

At the moment, relatives must donate a DNA sample for linkage testing to be done. They sign an informed consent form when they give blood indicating that they give their permission for the sample to be used for the presymptomatic testing of someone in the family. Usually the at-risk person requesting testing must arrange with relatives for samples to be sent to the laboratory or for neurological examinations to be conducted on critical relatives whose clinical status must be accurate; with all these preparations going on, the at-risk individual's desire to be tested is generally known and discussed in the family. Relatives have an opportunity to convey their feelings and, in some instances, they try to dissuade the individual from continuing with the test. Some parents have gone even further to exert their influence and have refused to give a DNA sample, thereby halting the test. One parent refused because the testing program in the locale did not provide adequate counseling and follow-up. Many of the testing centers have encountered other situations in which parents might be willing to give a DNA sample for one offspring's test but not for another: "Jane can take the news, John can't." Of course, once you know what pattern of the marker the disease travels with in that family, you do not need to retest the parent's sample for each child. Whose rights take precedence -- John, who says "I can take it, and besides, I want to get married"; or Jane, who says "Your arguing is depriving me of my test, and besides, I want to have a baby"; or the father who says, "I own my genetic profile -- you can't rob me of my genetic information and use it without my permission for purposes of which I don't approve."

A similar problem arises when identical twins arrive at the testing center and one wants to be tested and the other does not. Now who should hold sway? One center said, "We'll test you but don't tell your twin." It doesn't work. If you are free of the disease it would be almost inconceivable not to run to your twin with the good news. And if the outcome is HD, it's hard to explain uncontrolled crying as a chronic cold to people who know you well. Other testing centers confronted with this predicament consulted ethicists who gave them pronouncements that autonomy is higher on the scale of ethical virtues than privacy, so the centers decided to proceed with the test. But to my mind, autonomy or privacy may be irrelevant if the twin who is not part of the testing process and has not even had the benefit of counseling learns the truth and commits suicide. The immediacy of each individual's psychological reality must take precedence over abstract, theoretical values and issues. One cannot consult a guidebook for who should be tested and under what circumstances. The professionals giving presymptomatic test counseling must be trained psychotherapeutically to help determine the best solutions for individuals and families as a whole.

Another factor that is insufficiently appreciated is that when one person in a family is tested, the entire family is tested and all must live with the outcomes. Many parents of persons at risk feel guilty about and responsible for their children's risk status, even though they may have known nothing about HD when the children were born. In some families, three or four children simultaneously may be diagnosed presymptomatically. A parent who has spent fifteen or twenty years caring for an ill spouse now has a grim preview of the future: the prospect of caring for children as well, or knowing that the children may have to depend on the mercy of strangers. One woman said, "When my husband died after twenty-five years of illness, I felt like a light had finally come on at the end of the tunnel. Now I watch my daughter and see her movements and the light has extinguished."

Some of these decisions regarding who and when to test may be altered as we learn more about the meaning of genetic diagnostic information to those who are receiving it. During the 1970s, in Canada, several studies by Charles Scriver and colleagues showed that secondary-school children who learned they were carriers for the recessive gene causing Tay-Sachs felt stigmatized and somehow inferior to their classmates even though being a carrier was in no way injurious to their health.6 It was an emotional stigmatization. Will such responses be common? Some people insist, "Make genetic testing mandatory when couples get married." Others advise, "Integrate it into the genetic services, so that couples can be tested when they are contemplating pregnancy or are already pregnant." However, people disinclined to choose abortion might want to have genetic information before selecting their mate. A sickle cell screening program in Orchemenos, Greece, undertaken in the early 1970s before prenatal diagnosis was possible, found that 23 percent of the population carried the trait.7 Those discovered to be carriers were stigmatized and, as a result, they sometimes concealed their carrier status in order not to jeopardize marriage prospects. The net consequence was that the same number of affected babies was born as before the screening program. In two of the four matings resulting in the birth of an affected child, the women hid their carrier status, and in the other two the couples had children although cognizant of the risks. Once prenatal testing for sickle cell disease and thalassemia became widely available, carrier status became less of an impediment to social acceptance, even in predominantly rural, Catholic countries like Sardinia.8

Genetic misunderstandings and their implications. I am always surprised by the imaginative ways in which people can misinterpret genetic information. One common and very understandable mistake is the belief that at least one person in every family will be sick. In the Huntington's disease testing programs, people often arrive with the conviction that whether they will or will not get the disease depends on the fate of siblings. If my siblings are sick, my risk goes down; if they are old and healthy, my risk goes up. This is a perfectly reasonable misinterpretation given the way in which genetic inheritance is usually explained. Most genetic textbooks and consumer pamphlets teach principles of inheritance by showing a family of four children and two parents in which two children are affected and two are not. And doctors often explain risks by saying "half your children" or "one-quarter of your children will become sick." You must always say, "Each child has a fifty-fifty or 25 percent risk, regardless of the rest of the family." The day people in Venezuela became really confused about inheritance was the day the newspapers published such a diagram.

It is difficult to teach someone that "chance has no memory" and that whatever may have happened in a previous conception has no bearing on whether or not a child carries the HD gene. Each person has his or her individual risk and whatever happens to the rest of the siblings does not matter. I often ask people to flip coins during the counseling sessions to see, concretely, how it is possible to flip ten heads in a row. If they flip a coin which says they will get HD, it also gives that dire possibility some hard reality.

The idea that one's life or death is controlled in such a random way as a flip of a coin is appalling for most people. We try to make sense, make meaning of our lives. We try magically to control that coin toss by inventing rules governing who gets sick and who does not, but the fact remains: it is totally a random accident of fate which gametes meet, and in that moment the future is sealed.

Ethical, legal, and social issues.

There are many social, psychological, ethical, legal, and economic problems awaiting us that I have not even mentioned. Once we have improved capacity to diagnose disorders presymptomatically, many more individuals and families may face the loss of health and life insurance. They may be exposed to discrimination from employers and stigmatization and ostracism from friends and relatives. Predictive information can be fraught with dangers to individuals and to society. To address these concerns, the National Center for Human Genome Research, the National Institutes for Health, and the Human Genome Program of the Department of Energy have established the Joint Working Group on Ethical, Legal, and Social Issues associated with mapping and sequencing the human genome. It is the mandate of this working group to support research in these critical arenas and develop policy recommendations for the necessary protections that must be put in place as new genetic tests are being developed.

If there are so many personal, social, and economic hazards and successful cures are not assured, some people ask, why proceed with the project? How can we not proceed? Many who suffer from hereditary diseases already make huge economic sacrifices, already pay exorbitant psychological and social costs. I could not go to Venezuela and say to those expectant people, "Sorry, we've called off the research for the Huntington's disease gene because having the gene in hand is too dangerous and there is no guarantee of a cure." I am an optimist. Even though I feel that this hiatus in which we will be able only to predict and not to prevent will be exceedingly difficult -- it will stress medical, social, and economic systems that were already under a severe strain before the advent of the human genome project -- I believe that the knowledge will be worth the risks. We are learning from our experience with Huntington's disease and other disorders about the power of clairvoyance and the need for caution. We are preparing for the future when tests for breast cancer, colon cancer, heart disease, Alzheimer's disease, manic depression, and schizophrenia might well be available. For a while we may have the worst of all possible worlds -- limited or no treatments, high hopes and probably unrealistic expectations, insurance repercussions -- everything to challenge our inventiveness and stamina. But these ingredients will be, I hope, catalysts for change. The stakes are high; the payoff is high. I am reminded of a line by the poet Delmore Schwartz: "In dreams begin responsibilities."

REFERENCES

1. James Gusella, Nancy Wexler, P. Michael Conneally, et al., "A Polymorphic DNA Marker Genetically-Linked to Huntington's Disease," Nature, 306 (1983), 234-238.

2. Johanna M. Rommens et al., "Identification of the Cystic Fibrosis Gene: Chromosome Walking and Jumping," Science, 245 (September 8, 1989), 1059-1065; John R. Riordan et al., "Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA," ibid., pp. 1066-1073; Bat-Sheva Kerem et al., "Identification of the Cystic Fibrosis Gene: Genetic Analysis," ibid., pp. 1073-1080.

3. C.T. Caskey et al., "The American Society of Human Genetics Statement on Cystic Fibrosis Screening," American Journal of Human Genetics, 46 (1990), 393; B.S. Wilfond and N. Fost, "The Cystic Fibrosis Gene: Medical and Social Implications for Heterozygote Detection," Journal of the American Medical Association, 263 (May 23/30, 1990), 2777-2783; Workshop on Population Screening for the Cystic Fibrosis Gene, "Statement from the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis Gene," New England Journal of Medicine, 323 (July 5, 1990), 70-71.

4. Lori B. Andrews, "Legal Aspects of Genetic Information," Yale Journal of Biology and Medicine, 64 (1991), 29-40; N.S. Wexler, "Will the Circle Be Unbroken? Sterilizing the Genetically Impaired," in A. Milunsky, ed., Genetics and the Law (New York: Plenum Press, 1980); Nancy S. Wexler, "The Oracle of DNA," in L.P. Rowland, ed., Molecular Genetics in Diseases of Brain, Nerve, and Muscle (New York: Oxford University Press, 1989).

5. Symposium, "A Legal Research Agenda for the Human Genome Initiative," Arizona State University, Center for the Study of Law, Science and Technology, May 17- 18, 1991.

6. Reported in Marc Lappe, Genetic Politics (New York: Simon and Schuster, 1977).

7. G. Stamatoyannopoulos, "Problems of Screening and Counseling in the Hemoglobinopathies," A.G. Motulsky and W. Lenz, eds., Birth Defects (Amsterdam: Excerpta Medica, 1974), pp. 268-276.

8. A. Cao et al., "Prevention of Homozygous Betathalassemia by Carrier Screening and Prenatal Diagnosis in Sardinia," American Journal of Human Genetics, 33 (1981), 593-605.

9. Personal communication, Dr. Jason Brandt, Johns Hopkins Hospital, Baltimore, Md.

10. Amos Tversky and Daniel Kahneman, "The Framing of Decisions and the Psychology of Choice," Science, 211 (1981), 453-458.

11. Melissa A. Rosenfeld et al., "Adenovirus-Mediated Transfer of a Recombinant -Antitrypsin Gene to the Lung Epithelium in Vivo," Science, 252 (April 19, 1991), 431-434.

12. Mitchell L. Drumm et al., "Correction of the Cystic Fibrosis Defect in Vitro by Retrovirus-Mediated Gene Transfer," Cell, 62 (September 21, 1990), 1227-1233; D.P. Rich et al., "Expression of Cystic Fibrosis Transmembrane Conductance Regulator Corrects Defective Chloride Channel Regulation in Cystic Fibrosis Airway Epithelial Cells," Nature, 347 (September 27, 1990), pp. 358-363.

13. Natalie Angier, "Team Cures Cells in Cystic Fibrosis by Gene Insertion," New York Time, September 21, 1990, p. A1.