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Winding Your Way Through DNA Symposium

San Francisco, California
Saturday Afternoon, September 26, 1992

Neil Holtzman, MD, MPH

Neil Holtzman, MD, MPH, Professor of Pediatrics at Johns Hopkins University.

Thank you, Rick, I suppose.... You've given the beginning of my talk, so the audience will bear with me if there's some repetition.

Last night you heard that having a detailed map of his route across the United States enabled David Botstein to find the wallet he had inadvertently dropped out of an airplane east of Cheyenne. The scenario may be improbable but the point David made was not. A detailed map of the human genome will enable scientists to find all of the genes, all of our genes. This is the goal of the Human Genome Project as you've heard from Dr. Watson. It will increase our understanding of how the body works and what goes wrong in genetic diseases.

At the moment the path for applying that information to improve the outlook for those born with genetic disorders is more like a maze than a map. A maze, like the one used in animal experiments, in which hazards shock and are more plentiful than the reward. This afternoon I will spend the first part of my talk considering what we can expect and not expect from the Genome Project in improving the outlook for human diseases. Then I will turn to the hazards of genetic testing to individuals and society.

Let me begin, and here's where the repetition comes in, by describing the two categories of disease in which genes in the germ line, the eggs and sperm, play a role. First, diseases that play a role when a single gene goes awry, as explained by Dr. Singer this morning, we call single gene or Mendelian diseases, for the monk, Gregor Mendel, who first discovered discrete units of inheritance. Second, diseases whose occurrence depends on the presence of more than one gene, called multi-factorial disorders. (Dr. Singer's ras story deals with somatic cells in genetic diseases, you might consider cancer in that way, not germ line disease and I will not discuss the somatic diseases further.)

As you've heard from Rick Meyers, there are over 5,000 human traits that can be attributed to mutations in a single human genes, but some of these traits simply represent normal variation.

This slide shows some single gene diseases for which the genes have already been identified. I want to make three points about the diseases on this slide.

First, they include the most frequently occurring single gene diseases. Cystic fibrosis affects about one in 2,500 white children, and sickle cell anemia affects about one in 500 black children.

Second, the genes involved in these diseases were either discovered or were well on the way to discovery before the Human Genome Project officially began.

Third, each of these 12 diseases can be diagnosed by laboratory tests before symptoms appear, even in fetuses. But in only three of them, growth hormone deficiency, hemophilia, and phenylketonuria, can treatment correct or compensate for the genetic defect.

This pattern of being able to diagnose disease or predict its future occurrence before being able to treat its symptoms effectively will be repeated again and again as additional disease-causing genes are identified. The reason is simple: once a gene is identified it can be inserted into plasmids by recombinant DNA techniques and cloned, and you've heard all that. The large amounts of DNA that are manufactured in this way can then be used as a test probe to determine whether a person has a disease-causing mutation in the gene. Finding a safe and effective treatment, on the other hand, is much more difficult. I will return to the ethical consequences of this temporal gap between diagnosis or prediction on the one hand and treatment on the other in the second part of the talk.

Now if the genes responsible for the most frequently occurring single gene disorders have already been discovered, what is left for the Genome Project? Most of the single gene traits that do cause diseases, albeit rare ones, are waiting to be identified. Collectively they affect more people than the few frequently occurring diseases like cystic fibrosis and sickle cell anemia. Mapping the human genome will accelerate the discovery of genes for all of the remaining rare single gene disorders.

Mapping the genome will also lead to the identification of genes that predispose people to multi-factorial disorders. Many of these disorders occur much more frequently than any of the single gene disorders. We can view the discovery of these genetic predispositions akin to the discovery of risk factors for disease such as high cholesterol and cigarette smoking. If you have the risk factor your chance of getting the disease is higher than if you don't but you can have the risk factor and never get the disease or you can get the disease even if you don't have the risk factor. In contrast to high cholesterol and smoking, you can't get rid of your genetic predisposition. You can lower your cholesterol by diet or drugs and you can stop smoking, but you can't exchange bad predisposing genes for good ones, either now or in the foreseeable future. Telling people of their genetic predispositions may prompt them to get more frequent exams so that the disease can be caught early, or knowing they are at increased risk, people may be more willing to take steps to reduce their chance of getting the disease. But we still don't know many steps that will work or how frequently people will accept them.

The ability to map predisposing genes to specific locations on the human genome is proving far more difficult than mapping single gene disorders. One problem is that the multi-factorial diseases are not discrete entities as are many single gene diseases. The chance for a mistake in diagnosis is higher.

Another problem is that the same gene may not play a role in all persons afflicted with a particular disorder. As a result of such difficulties, reports of mapping genes for manic depressive or bipolar disorder and schizophrenia have been retracted and an association of a specific gene with alcoholism has been disputed.

Despite these problems, extravagant claims have been made by reputable scientists for the importance of the Human Genome Project. Daniel Koshland, a leading biochemist and the editor of Science, had the following to say at a genome conference in 1989. Koshland argued that no group would benefit more from the project than the homeless, since many of them suffer from disorders that would eventually be prevented or treated thanks to the Genome Project. This suggests that, contrary to fact, that the vast majority of people who find themselves out on the street have diseases like bipolar affective disorder and schizophrenia.

Despite the hype, the fact remains that by the time the Genome Project is finished, all 100,000 human genes will be located on specific chromosomes in sequence. This has a nice, egalitarian ring to it. Regardless of which deleterious genes any of us carries, they'll all be identified. But we have no assurance that people at risk for any genetic or gene-influenced disease are equally likely to derive benefit from the discoveries or that the benefits will exceed costs and risks.

I will consider three problems: applied research and development, pricing, and access.

Funds earmarked for the Human Genome Project will not be used to elucidate the function of genes as they are identified. Consequently, the potential benefit to people at risk for some diseases may be delayed or never realized. I doubt we'll see the same rush for capitalizing on the discovery of genes for rare diseases as we have for cystic fibrosis. It did not take long after the CF gene was found, about August 1989, before the rush was on to develop a test that could detect the one in 25 whites in the general population who are at risk for having children who are at risk for having CF. This is from February, six months later, 1990. Companies and a few medical centers are already selling such tests although they are not capable of detecting all CF carriers. Seldom will knowledge of the gene for a rare disease prove lucrative enough to stimulate commercial interest. One exception is the gene for growth hormone deficiency. Growth hormone is used...to treat children with a rare deficiency but it could also be used in healthy kids who are not tall enough to play basketball, professional basketball in particular. This use of genetic research to enhance normal function is one ethical problem that I will not comment on further, but you should think about it.

The next problem is pricing. With patent protection, manufacturers can fix prices artificially high on genetic tests and therapies as has happened with growth hormone. Originally intended to provide a reward for inventors, patents may not serve the public well in the genetic area. The discovery of the genes for many diseases which is an essential step in the development of genetic tests or effective treatments, is being accomplished by the investment of public funds in the Genome Project. The public does not hold the patents on these genes and seldom will in existing patent law. In many instances, Universities hold the patents as the recipients of public grants under the Genome Project. Due to changes in the patent law in 1980, a university can grant an exclusive license to a company to develop a product based on the patent held by the university. As a result of such a monopoly, the public, who through tax revenues paid for the project in the first place, could pay more than the costs justify when the product comes on the market. Unless health insurers agree to reimburse for these high prices, only the affluent will be able to afford the results. Any reduction in price that is possible, that a manufacturer--a monopolistic manufacturer makes--will be to maximize profit and not to make the products available to everyone.

This brings me to the final one of these three problems: access. It, too, is tied up with reimbursement for health care in the United States. Let us return to Professor Koshland's contention about the benefit of the Genome Project to the homeless. Even if he is correct, how the benefit would get to the homeless under the current reimbursement scheme is puzzling at best. As I will consider shortly, rather than finding the fruits of the Genome Project used for their benefit, those alleged to have genetic predispositions may find that they are used against them.

Given these problems, we have to ask whether three billion dollars planned for the 15 year Genome Project, assuming no cost or time overruns, is a reasonable allocation of scarce resources. Last night, Dr. Watson said we need more money for this enterprise, not less. If we can harness these discoveries to serve mankind without hazard and if there were no competing needs to be satisfied, I could not disagree. I also want to make clear that I'm referring only to the Human Genome Project and not questioning the development of recombinant DNA technologies which, as we've heard this morning, have had far-reaching and very important applications well beyond genetic diseases.

If it were true that non-genetic diseases were no longer significant problems we could argue with greater conviction that the investment in expanding our knowledge of the human genome was justifiable. In recent years, however, the greatest increase in age-adjusted deaths among Americans has been AIDS, now the 11th leading cause, and infections in the blood stream, now the 14th most frequent cause. Deaths from homicide and legal intervention have also increased and are now the 10th leading cause of death. The recrudescence of tuberculosis, the emergence of other infectious diseases, public health problems such as Lyme Disease and Toxic Shock Syndrome and the pernicious problem of antibiotic resistance as has been described by Dr. Cohen and Dr. Bloom indicate that we have not licked infectious diseases. As we heard from Dr. Bloom, infectious disease looms large in the Third World but when fewer than 10% of children in Houston have been immunized, as he told us, it is still a problem here.

We come finally to the potential misuses of genetic tests. Toward the beginning of the talk I indicated that tests to diagnose diseases or predict their future occurrence will be available long before effective treatments. What happens in this gap between detection and treatment? Let us answer this first for tests that are intended to predict future disease or an increased risk for disease in the person being tested. Consider Huntington's disease, a single gene neuropsychiatric disorder that begins insidiously at about 40 years of age and follows a progressively cruel course to death in ten years or so. There is no treatment but there is the predictive test. Would a person at risk, that is, someone who has a mother or father with the disease, want to know that he or she will get Huntington's? A positive test could be like a death sentence for some while for others it could relieve the anxiety generated by uncertainty. A positive result also means that each of the person's children has a 50% chance of having the disease.

Because the disease is untreatable, people with Huntington's disease who have a positive test result for it cannot obtain health insurance in the United States. Employers who know a person is at risk are unlikely to employ that person, partly because care will raise the cost of the employer's health benefits. A person with a negative result, on the other hand, may not be able to get health insurance whereas he or she was uninsurable when they knew the risk was 50%. Insurance underwriters call this "fair" discrimination. A person who has a greater chance of getting sick or dying soon, they say, has to pay more for protection. There may be some merit to this for life insurance but if we are all entitled to health care it is hardly fair for medical insurance. For Huntington's disease and many other conditions for which tests will be available, the person with a positive result will be denied insurance or have excluded from coverage the disease for which he or she will incur the greatest cost. This problem is not unique to genetics. Health insurers for many years refused to insure people because the occupation in which they worked increased the risk of disease.

Getting group insurance is progressively harder as this story talks about, for those who are or have been sick. Now, 60 years ago when Blue Cross started, private insurance provided broad coverage to many people because their individual risks could not be predicted. Almost everyone could be charged the same amount for health insurance. As it became increasingly possible to distinguish risks, some by predictive tests, others by epidemiological information on hazards of different industries, private insurance became affordable for fewer and fewer people. That is what we see today and we need something better.

I will now turn to the gap between detection and treatment for tests that are used to predict untreatable disease, not in the person being tested but in unborn children by prenatal diagnosis. Although couples may elect to continue the pregnancy when the fetus is found to be affected, I think it's fair to say that the technologies for prenatal diagnosis would not have been and continue to be developed if the alternative option of abortion was illegal. Under the Supreme Court's decision in Roe v. Wade, which still stands, the mother has the right to decide whether she wants to terminate the pregnancy for any condition prenatally diagnosed by about the 24th week. One concern is that couples will use prenatal diagnosis and choose abortion for disorders that do not appear until late in life, are not very severe, or for which the prenatal diagnosis cannot be made with certainty. As a result of the proliferation of tests as the genome is mapped, there will be more and more disorders in those categories.

In our culture, women's acceptance of prenatal diagnosis and abortion, from some of our studies and the work of others, correlates with the severity of disease and the certainty of prenatal diagnosis. Prenatal diagnosis, for instance, to select the sex of one's fetus and not in situations dealing with X-linked disease is seldom requested.

Some scientists and others believe that women should not have this right to bring children with disabilities into the world, if that's what they choose to do. And the reasons they give are either because their life will be too miserable to be worth living, a contention that is disputed by many people with disabilities, or because the support and care for such people is too costly, although it seems unlikely that abortion for severe genetic defects could be mandated in today's climate. A woman's right to choose freely can be eroded if insurance companies refuse to pay for the care of infants with diseases that could have been detected prenatally, or if public programs to assist programs in caring for children with disabilities are dismantled. In addition, if research-defined treatments for such disorders are not supported, prenatal diagnosis and abortion as an interim solution until treatments are found could become the final solution.

In conclusion, the Genome Project has been accompanied by a resurgence of interest in genetics. This is evidenced by the headlines that illustrate this talk. No doubt, the Project will greatly improve our understanding of how the human organism functions but the Project and the hype surrounding it may lead to exaggerated expectations that could undermine our social values. I've already mentioned the portrayal of homelessness and alcoholism as genetic problems and I'm now going to talk about something that apparently a number of people in the audience had raised this morning.

Here is a front page New York Times report of Department of Justice data claiming a family link to criminality. Although the article pointed out that the link need not be genetic, according to a more recent story in the Times, scientists working in the government are developing and I quote, "a violence initiative, which among other goals would seek to find biological correlates of violence in males, detecting them early in life and seeking to prevent their expression." Do we really believe that if there were genetic predispositions to homelessness, alcoholism or criminal behavior and companies marketed tests to detect them, that we could eradicate the problems? By looking for genetic solutions we are coming dangerously close to the eugenics of the early 20th century in this country and elsewhere. The emphasis on genetic causes is victim-blaming of the worst sort. It absolves the rest of us of social responsibility.

The Human Genome Project will provide a map for progress and also introduce a maze of problems. How the Project is conducted, who will profit from it, what might be foregone as a result of the public investment, and how individuals in society could suffer, are some of the questions I have raised. We are fortunate to have the opportunity to consider these questions at a relatively early stage in the quest for the complete genome. We should not take this past lightly.

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