It is only recently that medicine, biology and even health care have become not only a primary concern of society but also one of the central focuses of mainstream media. Indeed it is rare that a day goes by without an article on these topics on the cover of newspapers such as The New York Times. Whereas this type of information used to be reserved for people in the field, daily program's such as CNN's Your Health have brought the science and the debates around it to the center of our society. This essay shall focus on one of the most talked about, common and painful genetic disorders. After explaining what the symptoms and causes for muscular dystrophy are we shall reflect upon the moral, ethical and practical debates that surround the technology being developed for the prevention, screening and curing of the disorder.
The term muscular dystrophy is used generically to encompass several muscular disorders present at birth and probably all genetically inherited. These cause progressive weakness, disability and ultimately death which occurs in adolescence from secondary infections or intractable congestive heart failure (Complete Home Medical Guide, Pg 636-637). From a clinical point of view there are at least six major forms of the disease. Although from a clinical point of view there are differences between the different types, they all share the same pathological findings (Textbook of child neurology, Pg. 826). Duchenne dystrophy is the most severe and probably the best known (Complete Home Medical Guide, Pg. 637), it will also be the one studied in this essay.
The initial complaint in most boys with muscular dystrophy is a gait disturbance. This always happens before the age of 5 and usually before the children turn 3. Early symptoms such as toe-walking, frequent falling and delayed achievement of walking are usually dismissed by parents and physicians as simple clumsiness. However, the disease progresses to the point that the children have difficulty rising from the floor and have an obvious waddling gait. This decline in motor strength remains linear. The symptoms accentuate themselves between the age of 3 and 8. On average, functional ability declines rapidly after age 8. By their 9th year some become confined to the wheelchair and by their 12th year most cannot remain ambulatory (Clinical pediatric neurology, Pg. 182). Other symptoms include large and rubbery calf muscles and in Duchenne muscular dystrophy an IQ that is significantly lower than the average, the mean IQ of affected children being of only 85. More importantly the pelvic weakness that prevented them from rising from the floor can increase to such a degree that breathing becomes difficult and some patients can die of chocking.
Duchenne muscular dystrophy has a worldwide distribution, with a mean incidence of 1 per 3,500 male births (Clinical Pediatric Neurology, Pg. 180). The children lead a life ridden with difficulty and physical pain. While kids their age are seen running around playing, these boys rapidly loose functional use of their limbs. There are also many other problems associated with muscle wasting. To be sure that the child has the disease a muscle biopsy is usually done to check for dystrophin levels and confirm that the child does have DMD and not another disorder. Deterioration of vital capacity to less than 20% of normal leads to symptoms of nocturnal hypoventilation. The child awakens frequently and is afraid of sleep (Clinical Pediatric Neurology, Pg. 182). Because of infiltrations of fat in the muscle, enlargements of the heart are seen in around 80% of the patients and these also suffer many gastric problems such as sudden episodes of vomiting, abdominal pain and distention. The course of the disease is steadily downhill, death usually occurs in adolescence. The cause of death is not always clear, but respiratory insufficiency and heart failure are a contributing factor in almost every case.
Duchenne and Becker muscular dystrophies are variable phenotypic expressions of a gene defect at the Xp21 site. Becker form has a later age of onset and usually survival into adult life. The abnormal gene product in both dystrophies is a reduced muscle content of the structural protein dystrophin (Clinical Pediatric Neurology, Pg. 182). In Duchenne muscular dystrophy, the dystrophin content is less than 3% of normal. The gene is ten times bigger than any other characterized to date. It consists of 2 million base pairs. Its product, however, is a low abundance protein that constitutes only 0.002% of total muscle protein (Textbook of Child Neurology, Pg. 829). The elucidation of the gene defect in Duchenne and Becker muscular dystrophy is one of the most important triumphs of molecular biology. Using positional cloning, Kunkel his group located the exact site for the gene. After many steps which included isolating deletion-specific clones and using restriction enzyme maps, the cDNA corresponding to the complete muscle transcript was isolated and sequenced. By means of this cDNA, deletion mutations have been found in 65% of the boys with DMD. In other cases there have been point mutations or duplications in portions of the gene. There also seems to be "hot spots" in a region of the DNA since 40% of deletion starts in that same region (Clinical Pediatric Neurology, Pg. 182).
Duchenne muscular dystrophy is inherited in an X-linked recessive way although in up to a third of cases DMD occurs in families with no previous history of the disease. This means that the abnormal or disease producing gene is passed through the X chromosome. Furthermore, since it is recessive it can be suppressed if there is a complementary normal gene, namely another X chromosome. There are many implications to this. Since boys with DMD usually do not survive to have children, the disorder is transmitted through women who carry the gene. Since a woman has two X chromosomes, the malignant mutation on one of the Xs will be dominated by the normal gene. Since she is a heterozygous carrier she may transmit either of her Xs to her sons and daughters. Any son who inherits the mutant X will be affected, while any daughter that inherits it will, like her mother, become a heterozygous carrier. With each pregnancy in a family where a mother is a carrier and a father is unaffected, there is a 25% chance of having an unaffected daughter, a 25% chance of having an unaffected son, a 25% chance of having a carrier daughter and a 25% chance of having an affected son ("Giovanni Naso's muscular dystrophy page").
Currently there is no reliable mode of prenatal diagnosis or cure. For a series of reasons, diagnosis using DNA markers from amniocytes is error ridden and deletion mutants are detectable in only 65% of cases (Textbook of Child Neurology, Pg. 835). However, there is new hope for women in families with DMD. It was discovered that two thirds of known carriers had raised CPK (creatine kinase) levels. Furthermore new DNA tests can be used to verify if a mutation identified in a related male carrier is or is not present in the woman. This combination will predict correctly about 98-99% of the time if a woman is a carrier for the gene or not (Duchenne muscular dystrophy, Pg. 57).
Although life for kids and families with DMD is very hard and puts a toll on their spirits and hopes, recent technological advances show the promise of a better life, and possibly, a cure. In recent years the media has given a lot of attention to gene therapy. Some like Ronald G. Crystal of the Cornell Medical Center in New York city have said that "it is going to revolutionize how we treat patients" while critics say that man is being too arrogant and that this will ultimately lead to his demise (Science News, Pg 284). Before becoming prey to the numerous cliches fed to us we need to examine what the technology really is and what it implies.
Two different approaches have been developed in the pursuit of a cure for DMD. The first and oldest form is that of myoblast injections (The Economist, Pg. 103). This consists of taking defective myoblast -muscle cells- from muscular dystrophy patients and inserting the normal genes for dystrophin. The next step is to encourage these re-engineered cells to multiply and then reimplant them in the patient, hoping that they will synthesize dystrophin, the missing protein that spans the muscle cell's outer membrane. Although some trials have been successful (New York Times, Pg. 1A) the engrafments have been troublesome because the cells were very static and also because the effects of dystrophin are local ". This meant that treatment would require a separate injection for roughly every square centimeter of the body" (The Economist, Pg. 103).
Most researchers now think that the most promising way of curing this disorder is by shuttling the dystrophin gene to the muscle cells through the use of retroviruses (Wall Street Journal, Pg. B1-B2). This method consists of cloning the gene and incorporating it into a virus and then infecting the muscle cells with that virus. The challenge is to develop a virus with little or no toxicity that will "deliver successfully its cargo" (Science News, Pg. 284). Furthermore, with muscular dystrophy the problem is that the gene is so big that no virus seems to be able to fit all the DNA (Wall Street Journal, Pg. B2). Some researchers have constructed miniatures versions of the gene by splicing out promoter regions and "switches" that made sure that the protein was produced in muscle cells and where it is needed, not other cells such as liver cells (New Scientist, Pg. 24). These were replaced with simpler controlling mechanisms found in other genes.
"Successful gene therapy for both Duchenne's muscular dystrophy and cystic fibrosis requires the delivery and long-term expression of the appropriate gene to large numbers of cells throughout inflamed and fibrotic tissues" (The New England Journal of Medicine, Pg. 872). Although we have not yet developed this technology, promising new approaches of modifying vectors and implementing this gene therapy are under way (The New England Journal of Medicine, Pg. 872). In a world where science-fiction turning into history has become an almost daily fact it is almost certain that these minor technicalities will be resolved. The challenge, however, does not end with simply resolving them. Rather, the main concern becomes uniting the science with that other technicality which we call ethics.
When this technology is fully available we will be faced with the dilemma of whether we should use it, how we should use it, who should pay for it and who decides. In a world that revolves around profits and fiscal healthiness it is clear that insurance companies and consumers are going to have many differences. First, should insurance companies be allowed to overcharge women carriers of the gene?, should tests be administered systematically to screen for the gene? More importantly, when the technology is developed to effectively screen newborns, can insurance companies force people to take them? If the child proves to carry the disease, can they deny coverage at birth or again increase premiums? Many argue that this would allow for fairer premiums: those who will cost more should pay more, why should others pay? Yet, one cannot reduce the value of our lives to simple mathematical equations. Insurance rests on the principle that people pool their money for exactly this type of problem. If we start denying coverage and/or modulating how much each has to pay based upon his genetic profile then the basic covenant of insurance is violated and it becomes a simple instrument of profit.
This, however, simply scratches the surface of the debate. The main question reaches far deeper and touches upon the very essence of what it means to be human. To many there is no question as to whether gene therapy should be used. Before jumping to these conclusions, however, one should examine the disease carefully. Muscular dystrophy does not merely end at the disturbing pictures of young boys on wheelchairs, and at the smiling faces of children who will not live longer than 20 years. Simply browsing through the internet, one can see how much this disease has brought people together. In a world where people tend to compete against each other and usually divide, here is a disease that has created a cohesive bond among all those affected. Yes the disease is very difficult but does it not also add a dimension of life that those who are not affected often lack?
Furthermore, a society needs these differences to put people's lives in perspective. Oftentimes, we learn about ourselves and our world from people whose lives have been affected by such disorders and by their achievements. This essay and many others like it are an example of this. Because these diseases exist they compel us to think about ourselves and discuss what it means to be a human being. Every time we do this, we learn something new, understand a new dimension.
The other important question is where does it stop? Muscular dystrophy is a severe disorder and a cure for it will be a miracle for many. Nevertheless when gene therapy for is developed for MD will humans be able to stop the wave of other therapies that will use the same technology? Already, researcher have isolated a so-called obesity gene. Could the next gene therapy be one that will give all of us the figure, the blond hair and the blue eyes that every day fill magazine pages and television shows? If we do, then we also change what it means to be a human being.
Having said all of this, we cannot deny that a cure for muscular dystrophy would end a lot of pain and grief. What the previous discussion suggests is that we should be very careful in the way in which we use it. Again the question arises on whether insurance companies should be able to coerce people into having gene therapy by denying coverage if they opt not to for example. When dealing with this question one really needs to understand all that is involved. Many people believe that this is God's turf and that we should not intrude. Insurance companies cannot dictate people's lives in order to reach financial targets. If some of the people affected believe that there is an intrinsic value and beauty to life with or without a disorder then we are bound to accept that.
It is very hard, in the span of an essay, to discuss and even fathom such profound issues and dilemmas that touch upon the very foundations of what we believe being human means. However, if there is one lesson that one must learn before even beginning to deal with such issues it is the importance of knowledge and understanding. It is very easy for the cliches that surround us to sway us in the wrong direction. Before making any judgement one has to escape these cliches by first of all understanding what gene therapy really is and secondly by seeing how all its vast applications will affect the way people live. We have to take into consideration that we are talking about human lives and not mere numbers or case studies. Ultimately we need to set guidelines and laws to regulate the proper use of gene therapy. But these will not be very useful until people internalize the meaning and implications of this technology. The true challenge is here: to unite the science with the ethics.
Despite some dangers, there are good reasons to be optimistic about the ultimate success of gene therapy. Recent history in this field has shown that there is plenty to be enthusiastic about. The next step is to create the correct framework for this revolution in molecular medicine. For people to understand that science is no longer something reserved for the darker corners of the newspaper, but that its implications are very real, profound and that they will shape the way we live. One thing that we should learn from the people who make the web pages described above is to always remain hopeful. Perhaps, in the near future, those laughing faces on the pictures will get to keep their smile past their teen years.