What could be more heartrending than a mother's concern for her child--especially if the child is ill or tragically afflicted with some incurable disease? From the viewpoint of a parent, the concerns and priorities seem quite obvious: for example, seek whatever means might be available to treat and comfort the child. While all of us can readily sympathize with this parental imperative, are there things we can learn as outsiders in a college undergraduate class if we begin to examine the parent's dilemma more closely and objectively?
We could begin by dissecting the scientific as well as personal factors involved in a parental decision to seek treatment for a child with an incurable illness. Would students a priori expect the parents to first seek as much information as they can about the pros and cons of the treatment, or would students expect the decision to boil down to a simple matter of the heart and little more? What counsel would students offer the parents? To be in the best position to offer assistance or advice, what would students want to know about this case? What would they want to know about this disease? Is it really incurable? Are there potential therapies currently used? How would we find out? Whom do we talk to? What do we ask? Will we ever be able to find out enough information to make an informed decision? Or, getting back to the values of the heart, what does it matter what the experts say: "The child is mine and I want the best, no matter what!"
Here is a case dealing with the the scientific, societal, and personal sides of a decision involving an incurable genetic disease, muscular dystrophy. Students have the opportunity to explore key issues surrounding a parent's dilemma in making decisions affecting a child's welfare. Disparate factors can be dispassionately exposed and subsequently weighed in the decision. In the process, critical thinking skills and abilities for oral argument are also revealed and implemented. For the past few years I have used this case study in both non-science and science classes. It has worked well, as the students themselves uncover the scientific as well as the personal ingredients involved in making a critical health care decision. While the principals in this case are real people, all names have been changed in the interest of confidentiality.
The parents, Kim and Todd Davis, are both well educated and well off financially. They have two children, John and Mark, who are both stricken with muscular dystrophy. The prognosis is that their muscular systems will gradually deteriorate, resulting in an early death. Yet the advances of medicine hold out the promise of a possible cure in the foreseeable future with gene therapy. Closer to hand is the possibility that embryonic muscle cells from normal individuals might be injected into people suffering from muscular dystrophy, which could bring about partial relief for John and Mark. There are risks, however, as with any experimental method, such as the possibility of immunological rejection of the foreign cells.
This case is rich in its possible avenues for exploration. Although I have used it for biology majors, I normally teach it as part of a two-semester general biology course for non-majors where the focus is on contemporary problems. The format is a mixture of lecture, lab, and case studies. This particular case comes up in the latter half of the second semester when we study anatomy and physiology, focusing on the three themes of the nervous system, the endocrine system, and physical fitness. It is in the latter section, where cardiovascular and muscular systems are introduced, that this case is employed.
Case Objectives
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BLOCKS OF ANALYSIS
Students explore several key issues in this case: muscle and its normal and diseased state, the importance of money in the scientific research agenda, the scientific method, Food and Drug Administration procedures, and family health care issues. On occasion we have also discussed the animal rights issue and the importance of animals in research.
Muscle
Muscle structure and function is the central focus of the case, and the instructor must get to this point early in the discussion. The students will have developed some expertise by reading and from the lecture. Especially important in this discussion is the embryological development of muscle and what happens to people born with muscular dystrophy.
While it is not my intent to completely explore the structural or developmental properties of muscle, I do stress and illustrate the following points: healthy muscle tissue is made up of fiber subunits which collectively act as a pulley system within the body to move the body parts (i.e., healthy, functional fibers enable a person to do work and live a physically active life). However, in the case of Kim's sons, these fibers gradually break down and die, causing a weakening of the body's pulley system.
After the discussion has proceeded a while, the question of Dr. Hidi's therapy invariably arises. The point must be developed that muscle tissue is normally surrounded by satellite or myoblast cells; these cells are normally dormant, but if activated, they can fuse into tiny, functional muscle fibers. The significance of knowing what these cells are, where they come from, and how they might be therapeutically implemented are issues quickly grasped by the students; for example, healthy myoblasts might be able to rescue deteriorating muscle caused by some genetic error.
Usually the students are eager at this stage to speculate on methods of therapy not unlike those to be carried on by Dr. Hidi; i.e., the injection of healthy myoblasts into dystrophic muscle. However, when I begin to ask a series of specific questions related to the experimental protocol, the students usually conclude that more information is needed before therapy might be implemented.
My questions include:
These questions and many more become the focus of a later discussion in class involving the scientific method and the Food and Drug Administration (FDA).
During this discussion, we talk about one of the key characteristics of the disorder: weakness--the kind that impacts the ability of a child to rest on a toilet seat, take a regular school bus, or, even more frightening, fight a common cold. These observations illustrate the functional role of our body's skeletal muscle in controlling posture, mobility, and a huge assortment of vital activities. This particular topic has natural appeal to students, especially those interested in physical and occupational therapies. Moreover, most college students have a strong interest in athletics and physical fitness in general. They are eager to learn about the inner workings of muscle as well as its functional relationship to the body as a whole. From here, topics such as training, anabolic steroids, nutritional supplements; or conversely, atrophying conditions including immobilization and disuse, anorexia, and starvation might emerge. Ironically, because of the breadth of material, there is a risk that the class may become diverted and never return to the dilemma of Kim and her sons.
Muscular Dystrophy Is A Genetic Disease
Is the fact that Kim's sons have a "genetic" disease relevant to the present discussion of therapy? It may not be if the therapy under consideration is directed at rectifying muscle in some non-genetic, palliative manner; for example, a therapy that targets the ability of muscle to act as a functional pulley system but has no effect on the genetic constitution of the muscle. However, this is not the case here. Kim's sons have a form of inherited muscle disease called Duchenne muscular dystrophy (DMD), which is an X-chromosome-linked disease. The treatment proposed by Dr. Hidi involves injecting genetically normal muscle cells (with a normal X-chromosome) into genetically dystrophic muscle(s). Usually by the time this particular case study is used in my class, students have a working knowledge of genetics, which I describe as the study of information flow within the organism.
Characterized at three levels, genetic information first flows within the body's subunits--the cells. Information contained within a cell's genetic repository, DNA, is decoded to form the protein molecules necessary to give the cell structure and function. Students recall that the DNA within our cells comes in pairs so that we receive one copy from our fathers and one from our mothers. If the DNA information is defective in some way, a faulty or missing protein is likely to result. In the case of Kim's sons, their muscles are unable to make a particular protein that normally bolsters the integrity of muscle tissue. As a result, the muscle gradually deteriorates.
Another level of genetic information flow is from one generation to the next; i.e., fathers and mothers give one set of DNA information (within a sperm and egg, respectively) to each of their children. Hence, each one of our cells contains two sets of DNA, one from dad and one from mom. This DNA is packaged as chromosomes in our cells. However, in the case of the sex chromosome pair, male cells have an X-chromosome and a Y-chromosome while cells in female children have two X-chromosomes. Since Kim's sons are males, the DNA information in the X-chromosome, if faulty, will result in a faulty protein; in this case a missing protein. One way to replace the missing protein is to inject healthy muscle cells that contain normal X-chromosome DNA and hence have the potential to be decoded into normal muscle proteins including the one missing in Kim's sons.
The third level of genetic information flow is from cell to cell. When the body cells divide into two, they normally double the amount of DNA before dividing and then distribute an equal share in each daughter cell. This carefully controlled mechanism ensures that each of our body cells retain the same amount and kind of DNA. The implication in the present case is that the injected normal myoblasts will take root within the dystrophic muscle, grow and divide, and eventually form tiny muscle fibers, each capable of forming normal proteins. Hence the pulley-system characteristics of the muscles of Kim's sons will have been enhanced and strengthened. By discussing the three levels of genetic information flow as it relates to Kim Davis's dilemma, students see ramifications relating to the detection, expression, and treatment of a host of other genetic disorders.
Scientists and Money
At this stage an alarm bell may ring with some students. Why would a scientist who seeks to alleviate pain and suffering need political support? Aren't all medical scientists free from controversy? A discussion of scientists as human beings might ensue here. What are the driving forces in scientific discovery? How much is talent, and how much is dogged determination? (Earlier in the semester we read accounts in the popular literature and on video concerning the scientific method and such great discoveries as the double-helix structure of DNA and insulin.) What motivates Dr. Hidi? Where does his money come from? Is money to be made from Dr. Hidi's work if he is successful?
Since Henrietta Conklin makes the important point that Kim has contributed financially to Dr. Hidi's work, it may be appropriate at this stage to address some of the financial aspects of conducting scientific research. Students are quick to acknowledge that research costs money, but initially they have very little idea of the specifics. By the time they reach this point in the course, they do have a realistic view of the financial end of research. Previously, I will have held a discussion where I give each student in class a grant amounting to $200,000. After giving the students a moment or two to bask in their newfound riches, I begin the process of breaking the money down into realistic expenditures. The students are astounded by how quickly the funds are eaten up in mandated indirect costs, salaries, fringe benefit rates, and the spiraling costs of equipment and supplies. They become more amazed when we discuss the financial burden of using animals in a research project. Per diem costs for breeding and maintenance can quickly outstrip a sizable chunk of an investigator's funding resources. The point is routinely made in my classes that the degree to which a project is funded is often an indicator of scientific progress (or lack of it).
The Scientific Method and the FDA
Whether populated by science or non-science majors, from day one in my classes the students become acquainted with the scientific method. Many become quite adept at posing critical questions, such as one student in my class who blurted out: "Dr. Hidi, where's the data to justify injecting normal myoblasts into Kim's sons? You injected healthy myoblasts into muscles of mice and made many of them stronger, but these mice were weak because of a genetic defect to the nervous system, not a defect to the muscle system."
As we move to explore the possible methods of treatment, I remind students that implementing the scientific method means that through careful observation they have to identify the research problem, develop a testable hypothesis, and subsequently devise an experimental protocol that yields results, which may or may not support the initial hypothesis. Taking these steps in order, we summarize what we know of the problem. By now the class has a pretty good idea of the devastating effects of faulty DNA on the muscles of Kim Davis's sons; because of a missing protein, the boys are getting seriously weak. Hypothesis? It would appear that Dr. Hidi is working under the premise that a diseased muscle can be successfully treated by simply injecting healthy myoblasts into the muscle of Kim's sons. However, is his hypothesis sound given that his belief rests on his earlier mouse work? What does the class think?
If someone in the class hasn't highlighted the passage as yet, I refer back to the case where Kim's husband asks: "Did you read the research articles I left on the kitchen table this morning?" Unlike Dr. Hidi's work, the articles are about the muscle cell injection technique used on mice with actual inherited muscular dystrophy. An analysis by the class usually results in a major clarification of Dr. Hidi's experiments as well as the inherent weakness of his mouse model as preclinical justification for entering a Phase II trial--a trial which will include Kim's sons.
This brings us to the role of the FDA in the case. Since we have discussed the FDA procedures earlier in the course, students should recall the steps involved in the research investigator's receiving permission to initiate a series of controlled human trials (for background see Drugs-From An Idea To The Drugstore). FDA approval is based upon careful review of published and unpublished preclinical research findings, research that typically involves animals. In this case, it was the early mouse studies of Dr. Hidi and others that paved the way for clinical trial consideration. Subsequently, Phase I studies can be initiated on a small number of normal human volunteers for the very first time. In this phase of study, the relative safety of the therapy is the primary goal, not its therapeutic potential. Presuming that the myoblast injection technique did no real harm to the Phase I volunteers, Dr. Hidi would be free to try to recruit a limited number of patients for his Phase II trial.
We have now come full circle. What should Kim do? Dr. Hidi has announced that he needs dystrophic boys like Kim's sons to fill a Phase II pool of patients. In this case, the FDA is looking not only for evidence of safety but effectiveness as well. If the therapy fairs well in Phase II, a more comprehensive Phase III investigation can ensue, which if successful opens the door for routine public use.
Does the reader have enough information to judge whether Kim should or should not enroll her sons in Dr. Hidi's Phase II trials? Most of my students come down on the side that Kim should wait for more conclusive information before enlisting her sons. They argue that Dr. Hidi's preclinical mouse studies are not convincing evidence to embark on a Phase I study, much less proceed to a Phase II study. They become progressively more comfortable with their decision as the case study is broken down into its component parts. What seemed at first to be a quick emotional decision becomes a matter of weighing the evidence.
Family Health Care Decisions
The above blocks of analysis are often relatively distinct units of discussion for the class. However, the topic of health care and its impact on the family may crop up throughout the discussion. If the topic isn't covered earlier, it surely will dominate the class as the case comes to closure.
In addition to coping with the immediate problems of her sons' health, Kim is facing a deadline involving a potential treatment of her sons' disease. The decision isn't a simple one. As revealed from the conversation between Kim and her husband, there may be more to the therapy than meets the eye. Kim refers to "all this stuff in the papers about Dr. Hidi. He isn't even a medical doctor." What stuff in the papers? Are there questions about Dr. Hidi's credentials? Under normal circumstances how do parents sift through information about doctors and treatment in order to make an informed decision?
From the view of the parents, the process may be mind-boggling, even detrimental to domestic peace and harmony. One parent may want therapy regardless of the consequences, while the other may want more information. Emotions can run very high. Kim and Todd appear to have much at stake as marriage partners and as the final arbiters of their sons' health care decisions.
My class meets two times a week on a Tuesday and Thursday schedule, with 90-minute class periods. I hand out the case, say on Tuesday, with only a few words of introduction, telling them to bring in a one or two page double spaced essay the following Tuesday. The essay should explain what Kim and Todd Davis should do and why the student has made this decision.
In the Thursday class period which intervenes, I give a lecture/discussion dealing with normal muscle structure and function. Here I cover the differences in muscle fiber type in marathon runners and weight lifters, and what happens in training. The text reading on the muscle system helps set the stage for the case.
On the day of the case, I collect the student essays and spend the period in discussion. The first questions I ask to begin the case are open-ended and general. "Who wants to talk about Kim Davis? What do we know about this case?" As with other cases I run, I go with the flow of student interest. However, either at the end of this period or more frequently at the beginning of the next period, I do a 20 to 30 minute structured wrap-up of the case. This is a mini-lecture with overhead projection which focuses on the key issues of the case that I wish them to understand. I believe closure and summary are essential in cases.
Ackowledgements: Publication of this case on the web was made possible with support from the National Science Foundation (NSF Award #9752799).