The Line That Cant Be Crossed

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The medical establishment is unlikely to develop any eagerness to assist in terminating pregnancies based on complex or cosmetic traits, especially those that are not even sure to happen. However, physicians are more likely to be responsive to wishes of parents who want to terminate a pregnancy involving a condition that will lead to a very early, painful death for an infant. For many of the other areas out in the middle ground, it is the job of the medical genetics community to educate the parents, to offer insights into possible consequences of different choices, to provide them with long-term in addition to short-term views of the situation they face, and to inform them about the best-case and worst-case scenarios. In the end, though, the decision falls to the parents, not to the medical genetics professionals.

Every case is as unique as the individuals caught up in the situation. The combination of the parents, their stages in life, their individual personal and medical histories, and the context in which they live, can result in very different decisions being made relative to exactly the same test result. Something people have to be able to take into account in making these decisions is that the person they are today, and the issues that drive their decisions today, will likely change over the course of a lifetime. Thus they may need assistance in seeing just how their current circumstances, as well as their possible future situations, color their decisions.

People have substantial differences in what they can tolerate, different limits beyond which they cannot go. Some hit their limit when faced with terminating a pregnancy. Others hit their limit when faced with watching their baby die a long, slow painful death. Some hit a limit when faced with raising a child whose needs they know they cannot meet in a society that too often fails to live up to the ideal of offering a loving alternative home for such a child. So many factors contribute, including financial status, presence or absence of a social safety net to help a family cope, mental illness, alcoholism, and the presence of other family members who are desperately ill. A diagnosis of Duchenne muscular dystrophy in a child might well mean one thing to a young, happy, healthy, financially secure couple going through their first pregnancy in the context of a very supportive extended family but mean something quite different to a couple struggling with unrelated heath problems in the parents, major financial problems, lack of support from family or friends, and another child in the family suffering from more advanced stages of the disease.

Even trisomy 18, which might seem like a simple case because it represents the severe end of the phenotype spectrum, can elicit a broad range of responses. In the story at the beginning of the chapter, the parents wished they had had the information they needed to save their baby from unnecessary pain. Other parents, when receiving the news of trisomy 18 as a result of prenatal testing, terminate the pregnancy because they feel that it would be tantamount to child abuse to put an infant through what they know is coming. However, we know another woman who bore her trisomy 18 daughter and went home to sit and rock with her until she passed away, a font of maternal love, calm, and acceptance that many others have no capacity to achieve.

Some see a decision to terminate a pregnancy as a selfish decision that does not consider what the child's perspective might be. Some, though, who see themselves wishing they could die quietly in their sleep instead of lingering on in lengthy pain, have that same perspective of their child's life. Several years ago, Julia met a young man who considered his parents to be guilty of criminal negligence for failing to terminate the pregnancy that produced him and, a whole host of medical problems, when they knew that any child of theirs would be at fifty percent risk of inheriting the trait that ran in the family. Yet his father must have had a very different view of the situation, suffering the consequences of a medical condition and deciding that the positive aspects of his life so outweighed the problems that he would be willing to pass both life and this trait along to his child.

For each of us, there is an ethical brick wall that would stop us dead in our tracks if we ran into it. Fortunately, most of us are never faced with our own brick wall, and thus we do not even know where our real limit would be if we were put to the test. For those who get the news that there is a problem, there are amazing differences in what that brick wall turns out to be for different people.

For some, the act of terminating a pregnancy would be the thing too terrible to contemplate, to take a life or to fail to at least give the child a chance.

For others, to continue the pregnancy is the

Ii, i, i, i, i, i, i, ! ,[ thing they would never be able to forgive 111111111111111 themselves for, to bring a child into too brief 111111111111111 a life, one filled with pain in which their needs 111111111111111 are desperate but cannot be met. Either deci-111111111111111 sion represents a heartbreaking way for the i' i' i' i' I' i' i' i None of us will live with the consequences

' I' I' I' I' I' I' I' that fall upon someone else's family when they i' i' i' i' i' i' i' i make reproductive decisions of this kind, invariably profound and painful in their far-reaching implications. So the role of modern medical genetics is to allow people to make decisions that are as fully informed as possible. However, the role of modern medical genetics is not to make the decisions for the family. Those who will live day in and day out, with the child or with the absence of the child, are the only ones who can know just where they will reach that boundary beyond which they cannot go.

American Sign Language sign for "I love you."


The scene on the screen in the conference room looked just like a home video, a movie showing a beautiful briard dog named Lancelot walking into a dimly lit room. The place seemed a bit crowded, with disarranged furniture scattered about. The audience in the conference room watched, spellbound, almost holding their breaths, as the dog made his way through the room, carefully avoiding objects as he swung his head around in an odd manner to scan the area ahead of him with his right eye. He daintily picked his way through the obstacle course, the film stopped, the lights came up, and a few quiet spontaneous cheers could be heard over the applause that broke out around the room. Several of the rational, objective researchers in the room had lumps in their throats as they listened to the conclusion to the presentation. Gene therapy treatment of Lancelot's right eye when he was four months old had effectively cured a canine model of Leber congenital amaurosis, a severe form of early childhood blindness that is incurable and may be diagnosed in humans in the first year of life. Those attending the talk had just witnessed a medical miracle: a "blind" dog that could walk through a crowded, unfamiliar room and successfully avoid contact with objects. Lancelot could see with his treated right eye! Lancelot and some of his relatives develop vision problems because of a defect in a gene called RPE65. Since both copies of the gene are defective, the obvious approach to gene therapy was to put a good copy of the RPE65 gene into the cells of Lancelot's eye. The strategy proved valid when the three blind puppies who were treated turned out to be cured, and they stayed cured! The movie starring Lancelot has played to audiences of scientists from around the world, and Lancelot has even visited Capitol Hill to attend a congressional briefing on gene therapy. To the scientists in the conference room, the concept of being able to use this approach to cure blind children was emotionally compelling in addition to being scientifically attractive. The general approach looked as if it might be usable for some other recessive forms of inherited retinal degenerations. However, many gene therapy projects have not yet arrived at such dramatic successes. Why can't all of the other diseases in need of gene therapy simply be treated in the same way as the briard dogs were treated? Not all diseases can be treated this way because there are a broad array of technical and strategic issues to be sorted out that differ from one disease to the next and from one gene to the next. In this chapter, we want to show you a bit about how gene therapy works and what some of the issues are that keep gene therapy researchers in their labs burning the midnight oil in search of answers.

After great expense of time and resources on the part of many really, really smart people, we finally know the sequence of the human genome (and many other genomes, as well). The genes have been found (well, many of them, anyway). We are starting to find out what some of the gene products do. Biochemical pathways are coming together that provide us broad conceptual insights into a variety of pathogenic processes. Those of us who consider this a beginning, not an end, now face the critical question: What do we do with all of this knowledge? How do we convert all of these advances into help for people who are not adequately helped by the current state of medical knowledge?

We have seen some ways in which insights into new genes and new biochemical pathways have led to dietary management in disorders such as PKU or standard pharmaceuticals derived from information gained from genes for some kinds of cancers. However, the hope that comes from successful gene hunts points in the direction of gene therapy, the therapeutic use of the discovered genes themselves, and not just the knowledge gained from finding those genes. Earlier, we talked about the use of hydroxyurea to turn on expression of fetal hemoglobin in individuals with sickle cell anemia. In the future, we expect that gene therapy will include both introduction of genes into cells in the body and use of inducing agents to alter the expression of genes that are already there.

WHICH GENE SHALL WE USE? Gene Replacement Therapy

When the cystic fibrosis gene was discovered, the concept of gene therapy seemed pretty straightforward: put a copy of the CFTR gene back into individuals who have no functional copy of the CFTR gene. As soon as we say that, though, a lot of questions arise and we realize that there are actually many issues to be resolved in designing a gene therapy treatment. The first question that arises is: Which gene are we going to administer to the patient? It might seem as if the answer is obvious: put back a good copy of the gene that is defective. It may be that simple in the case of single-gene recessive disorders in which the disease results from loss of the function of the gene product. In fact, that is exactly what happened when the therapeutic version of the RPE65 gene was put into Lancelot's eye: a simple replacement of something missing (Figure 35.1). There are several kinds of recessive retinal degeneration caused by defects in both copies of a single gene that could likely respond to almost exactly the same therapeutic protocol, with almost the only change being the choice of which gene to put into the eye. Another obvious situation for gene replacement therapy is that of individuals who are lacking one of the key blood clotting factors. Like the eye, disorders of the blood provide a more delimited treatment problem because it is possible to treat blood cells without having to treat the whole body. Although gene therapy for blood clotting disorders might not seem like the highest priority given the existence of treatment through administration of the protein, the need to improve treatment of blood clotting disorders is driven by a variety of clinical factors including the continuing potential for contamination of proteins isolated from blood products.

Gene Suppression Therapy

In the case of dominant diseases (remember the concept of the monkey wrench), there is already one good copy of the gene present in the cell and

_ FIGURE 35.1 Gene replacement therapy adds back a functional copy of a gene in cases in which the disease results because defects in both copies of the gene result in loss of the cell's ability to carry on the functions normally handled by the product of that gene. In the case of the briard dog Lancelot, many good copies of the RPE65 gene were added into his eye in the vicinity of the retinal pigment epithelium cells that lacked the RPE65 protein activity that normally takes place there.

putting in more good copies of that gene may not help the situation. However, the situation can be helped by therapeutic approaches aimed at getting rid of the unwanted monkey wrench or the by-products of its misbehavior. So if the problem involves a toxic by-product, the use of gene therapy techniques to reduce the amount of a specific RNA can lead to reducing the amount of gene product being made. Scientists have successfully used an enzyme called a ribozyme (an RNA-based enzyme) to eliminate RNA from one gene while leaving other genes intact. In this case, the experiments were performed on cells growing in culture but these experiments showed that this approach can suppress the expression of an aberrant form of collagen that leads to osteo-genesis imperfecta. In other approaches, small interfering RNA technology can reduce the amount of transcript coming from the offending gene by putting in a small RNA whose sequence is complementary to the sequence of the mRNA produced by the disease gene allele. Because of the sequence complementarity, the small interfering RNA can bind to the mutant transcript and get the cell to destroy the RNA coming from the disease gene (Figure 35.2). In some cases, it is conceivable that the small RNA can be designed so that the transcript from the disease allele will be destroyed at a higher rate than is the transcript from the normal allele, allowing for the possibility of reducing the amount of a monkey wrench while still allowing for some normal protein to carry out the normal function. Other strategies work at the level of the gene product, by adding in a gene whose product will chemically activate or inactivate the problem gene product.

Complex with siRNA binds to RNA "A" based on sequence complementarity but does not bind RNA "B"

Cellular systems chew up pieces of RNA "A" that have complexed with siRNA and leave single-stranded RNA "B" alone, so that levels of message A and protein A end up reduced.

__ FIGURE 35.2 Gene suppression therapy. If the problem can best be solved by reducing the amount of a gene product (or its activity levels) a variety of technical approaches can be used. Small interfering RNAs can trick the cell into digesting and getting rid of RNA to which it binds and thus reduce the amount of the gene product in the cell. In some cases, it may be possible to design the small interfereing RNA so that it will selectively reduce the disease allele while leaving some of the normal allele present to produce the normal gene product. Someday it may be possible to fine-tune the use of promoter regions to control the level of expression of specific alleles of a gene.

End-Run Gene Therapy

In some cases, we may be trying to compensate for a problem that is too genetically complex to tackle at the point of the disease gene itself; in other cases, the trait may not even be genetic in its origins. In such cases, we may need to simply bypass the whole issue of which gene (or what else) is causing the disease, or even how many genes are involved, and target some other aspect of the disease pathology (Figure 35.3). Sometimes what is needed is to add a different gene that can supply a function that improves the body's ability to put up with the damage being caused, or that provides a mechanism to assist the body in recovering from damage that has been caused. An exciting example of this kind of "end-run" gene therapy that completely bypasses the

Damage to heart muscle Growth of new blood because of vessel blockage vessels restores blood supply to heart muscle

Damage to heart muscle Growth of new blood because of vessel blockage vessels restores blood supply to heart muscle

FIGURE 35.3 End-run gene therapy. In some cases, gene therapy can be used to treat a disease without going after the primary causes of the disease. In cardiovascular disease, gene therapy projects have encountered some interesting successes. One study used gene therapy to provide an APOE gene that produces an APOE protein that helps reduce "bad" cholesterol, resulting in disappearance of plaque attached to blood vessel walls. This artist's conception shows how uses of growth factor FGF1 can cause new blood vessel growth in a local area of the heart to restore blood supply to a region previously supplied by a blocked vessel. Successes of this kind have been seen in animal models, and some early human studies in gene therapy of cardiovascular diseases are ongoing.

original cause of the damage can be found in cardiovascular research. Researchers have shown that a growth factor called FGF1 can be used to stimulate local growth of new blood vessels to supply heart muscle in cases in which blockage is reducing the blood supply to the heart. In patients with blood vessel blockage, the combination of genetic and environmental factors contributing to blockage and damage to the heart muscle is likely complex and different for different individuals. Yet a single treatment approach that goes after the secondary problem of getting a blood supply to the heart could completely ignore the difference in underlying causes among the patients and successfully restore oxygenation of heart muscle.

Supplemental Gene Therapy

In some cases, tissues in the body simply need to be making more of something they already make. The item to be supplemented is not missing and the gene is not mutated. One of the situations in which this approach is being used is to get cells to make the proteins necessary for the formation of new bone material (Figure 35.4). In these cases, the patient does not have a defect in bone formation but rather has an injury of some kind that is more than his own body can heal. Gene therapy treatment of skin cells with bone mor-phogenic protein before placement of the cells into a region of bone erosion in periodontal disease can lead to formation of new bone in the region. Another approach places the gene therapy agents into a gel placed at the

Genes that will direct synthesis of new bone to heal the break are contained in a gel that allows slow release over the long time span needed to relace bone.

FIGURE 35.4 Gene supplementation therapy. An example of this strategy is the use of gene therapy agents that can induce cells in the bone to manufacture new bone. This is especially important in cases of severe fractures and fractures that do not heal well. By embedding the gene therapy agents in a gel at the site of the break, it is possible to have slow release of the DNA and gradual expression of the relevant genes over the extended time period needed for bone healing.

FIGURE 35.5 Supplemental gene therapy. Another use of supplemental gene therapy is to boost the ability of the patient to survive higher levels of chemotherapeutic agents being used to attack the tumor cells. A similar strategy might reduce the hazard of living or working in a contaminated environment.

point of a break in a bone, with gradual release over time resulting in sustained expression of the genes being used in the treatment.

Cleansing Therapy

During our lives, we suffer a variety of exposures that can be directly harmful or can increase our risk of things such as cancer. As we learn more about the normal mechanisms used by the body to eliminate toxic substances, more about biochemical pathways that can convert toxic substances into safe (or safer) substances, and more about ways to get compounds pumped out of cells or excreted from the body, we gain the potential to use gene therapy to protect us from exposure or to clean up our internal environments once we are exposed (Figure 35.5). An intriguing concept in cancer therapy is to put a gene into bone marrow cells that increases their resistance to the effects of anticancer drugs. This is important because some of the worst side effects in cancer treatment result because of key cells such as those in the bone marrow being damaged along with the cancer cells. If the bone marrow cells can resist the chemotherapeutic agents by pumping them out of the cell, the tumor

Cells in bone marrow use multi-drug resistance protein to pump out anticancer drug and stay healthy.

FIGURE 35.5 Supplemental gene therapy. Another use of supplemental gene therapy is to boost the ability of the patient to survive higher levels of chemotherapeutic agents being used to attack the tumor cells. A similar strategy might reduce the hazard of living or working in a contaminated environment.

Cells in bone marrow use multi-drug resistance protein to pump out anticancer drug and stay healthy.

cells could be attacked with higher doses of the drug than the patient would naturally be able to tolerate. Approaches of this kind have also been discussed as a preventive measure in cases in which occupational exposures to undesirable chemicals can be anticipated.

In some cases, especially with cancer, what we really want is to be able to destroy specific cells while leaving the surrounding cells intact. An especially ingenious idea was developed by researchers who want to use their magic bullets to destroy malignant brain tumor cells while leaving the surrounding brain cells untouched. Brain cells are not usually thought of as growing or dividing, so a virus that infects only actively dividing cells can be used to deliver the gene therapy agent, which will only be taken up by the actively dividing tumor cells. Administration of an antiviral drug called gancyclovir will expose many of the brain cells to the gancylcovir, but it will specifically kill only those cells that have taken up the virus, so the tumor cells will die but surrounding tissues will remain intact (Figure 35.6). This concept, that cell death will occur only where two separate events coincide, resembles a process in current use in cancer treatment. In this process, low-level radiation administered from multiple different directions spares the surrounding tissues while killing only those cells present at the point where multiple radiation beams come together at the same place to result in a dose high enough to kill the cells.

None of these categories of gene therapy are categories that people in the field use when they talk about gene therapy. If you encounter a scientist at a cocktail party and start to talk to her about end-run gene therapy, you are likely to get a blank look because, as with our terms "absent essentials"

FIGURE 35.6 Magic bullet therapy. Many different strategies are being developed for being able to target therapy in such a way that only the tumor cells die while the normal cells remain healthy. One strategy is to use two different therapeutic agents that are each benign alone and kill cells only where both agents are present. Use of a gene therapy virus that can only infect dividing cells will tag tumor cells while sparing surrounding nondividing cells. A secondary treatment kills only tagged cells. This strategy would not work in many tissues of the body.

Magic Bullet Gene Therapy

Gene thera age

Gene thera age

FIGURE 35.6 Magic bullet therapy. Many different strategies are being developed for being able to target therapy in such a way that only the tumor cells die while the normal cells remain healthy. One strategy is to use two different therapeutic agents that are each benign alone and kill cells only where both agents are present. Use of a gene therapy virus that can only infect dividing cells will tag tumor cells while sparing surrounding nondividing cells. A secondary treatment kills only tagged cells. This strategy would not work in many tissues of the body.

Gancyclovir and "monkey wrenches," these are terms we use because we find them useful to encompass concepts that tell us about different gene therapy strategies. They are not terms that the other scientists use when they talk to each other about gene therapy.

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100 Health Tips

100 Health Tips

Breakfast is the most vital meal. It should not be missed in order to refuel your body from functional metabolic changes during long hours of sleep. It is best to include carbohydrates, fats and proteins for an ideal nutrition such as combinations of fresh fruits, bread toast and breakfast cereals with milk. Learn even more tips like these within this health tips guide.

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