by
Michael S. Hudecki
Department of Biological Sciences
University at Buffalo, State University of New York
Named after the German neuropatholgist Alois Alzheimer (1864-1915), Alzheimer's disease is currently an incurable medical condition affecting a significant percentage of senior citizens worldwide. Experts estimate that approximately 10 percent of those over 65 years of age and half of those over 85 are afflicted. Moreover, research has demonstrated that about 50 percent of Alzheimer's disease is caused by a faulty gene(s), presumably affecting the expression of specific brain proteins such as beta-amyloid.
This discussion case explores the scientific process involved in implementing an animal model in the study of Alzheimer's disease. The students read a short paragraph describing a study in which the brains of "trained" mice were injected with beta-amyloid fragments, which subsequently caused them to forget their tasks. The paragraph is a very short New York Times story reporting on an experimental study originally published in the Proceedings of the National Academy of Sciences, USA (Flood 1991). Based on the short description provided, students are asked to identify relevant components of the scientific method, i.e., problem, method, results, and conclusions. All students are generally able to accomplish the assignment in the allotted 20-minute time period, after which I initiate a class discussion.
I originally used this case in a weekly freshman seminar course, History of Contemporary Biology, with no more than 20 first-year undergraduate students. While most were science majors, a significant proportion of the students were arts and humanities majors. More recently, I have incorporated this case as a regular feature in my two-semester non-science majors' course, Perspectives in Human Biology. This particular case comes up at the beginning of the second semester when we focus on the human nervous system. During the first semester of the course, the students develop a working knowledge of biological principles and the scientific method directed at a range of contemporary human biology issues.
Scientific Method. Although the class size varies, I initiate each discussion of the case by asking students to define the problem being investigated. Using a blank over-head projector transparency, I label "Problem" on top and wait for student responses. Students offer information on memory loss and Alzheimer's (as well as disease expressions involving amyloid brain plaques and the debilitated status of the mouse model). Very quickly, I am able to fill up the transparency with student feedback. Through dialogue and by drawing on their prior academic and personal experiences, students eventually group and refine responses into a manageable number of research problems. In broad terms, the consensus of the class is that the central problem is Alzheimer's disease (and its attendant memory loss). On the other hand, many students narrow the problem and focus more on determining the unknown etiology of the disease (i.e., amyloid protein). This part of the exercise yields both general and specific characterizations of the research problem at hand.
After spending sufficient time determining the problem, we move next to the experimental method. Using a new transparency with 'Method' written on top, I ask students "What did the scientists do to address the research problem?" and record the wide range of responses they propose. Some students immediately begin to describe the amyloid injection process, whereas others concentrate on the "training" phase of the study.
Although various methods are suggested, usually the class agrees that a "maze" is needed in which there is an incentive or reward for navigating the configuration. Consequently, the "trained" mice are thought to be suitable test subjects for the amyloid protein injections. These mice would be tested again using the maze/reward configuration to determine the amyloid's effect on memory. After further discussion, the class generally concurs that the critical result of the study is whether there is a change in the ability of the injected mice to navigate the maze successfully.
Before we begin discussing the critical results of the study, the class must decide what makes a proper "control" for the study. At this juncture I typically ask "How do we know that amyloid injection causes memory loss in the mice?" I then begin to develop a list of control (as well as further experimental) groups of mice for the study. I find this particular phase of the discussion both enjoyable (because the students by this time are really into the analysis of the case) and challenging (because I need to pay particular attention to each suggested control and the inherent rationale of its inclusion).
As a class we expand the study to include a growing list of groups: control groups of injected but not trained mice and mice that were injected only with the watery vehicle of the amyloid (sham group)--and an expanded range of experimental animals including males and females, young and old, and treatment groups composed of synthetic and natural amyloid protein fragments. Another offshoot is a discussion of how many animals should be included in each group. One or two? A dozen? Hundreds? At this point we are able to discuss both statistical significance (what it is and how it is used) as well as the cost of conducting any large-scale study involving animals.
Nervous System and Related Diseases. In the early phase of the class discussion, the brain is the natural focus because of the subject of the case. Through a dialogue led by the instructor, key components of the nervous system can be identified, including the sensory, motor, and association areas and pathways of the brain. Further discussion of the case problem also brings up the concept of memory; this neuro function is highlighted both as a short-term and long-term capacity. Once the students recognize the brain's central role in the healthy functioning of the body, they can easily speculate on the consequences of having plaques of amyloid protein distributed within the brain's neural pathways. From here, we can come to grips with the scientific and psychological manifestations of Alzheimer's disease.
On the scientific side, the class learns that Alzheimer's disease is a deterioration of cells within the brain that leads to loss of memory and other bodily functions. The students also see that the build-up of amyloid protein within the brain is likely a contributing cause of the disease (or at the minimum correlates with the disease's progression). On the behavioral side, several students often have relatives or family friends that have been affected by the disease. With gentle prodding, I ask them to share the behavioral manifestations of the disease with the class. In this manner, the research problem not only has a scientific underpinning, but takes on a personal dimension that everyone in the class can identify with, i.e., the disease could take root in my father, my mother, my spouse, my best friend, even me.
Toward the end of the case discussion, I point out specific websites on the disease. For example, the U.S. National Institutes of Health website at http://www.nih.gov is a good source of basic and clinical research information on Alzheimer's. The FDA website at http://www.fda.gov contains valuable information on current and anticipated drug trials relevant to Alzheimer's treatment. To no one's surprise, there is a growing interest in the private sector in the cure and treatment of the disease. The privately funded Alzheimer's Association website at http://www.alz.org offers news ranging from on-going research to fund-raising activities.
Time permitting, other neurological disorders might be introduced in tandem with the Alzheimer's discussion. For example, demylinating disorders such as multiple sclerosis and amyotropic lateral sclerosis might be briefly reviewed within the context of problem-based research. Neurological disorders involving neurotransmitter deficits such as Parkinson's disease might also enter into the problem phase of the discussion. By including these disorders within the case discussion, students are better able to appreciate how the scientific method of inquiry is readily applicable to a whole host of biomedical problems, not just Alzheimer's disease.
Animal Model Systems. This particular case focuses attention on the laboratory mouse as a model system to address the problem of Alzheimer's disease. Specifically, mice are initially trained in a box with an electrified floor that delivers a shock if the mice do not actuate a "reward lever" in a specified time. With repeated training sessions, the mice quickly "learn" to travel the length of the box and avoid getting shocked. Subsequently, the "trained" mice are subjected to injections of amyloid protein fragments and then re-tested to determine if they are able against time to navigate the box without being shocked. From my recent experiences using this case, students accept the rational use of animals to achieve a research aim, especially in cases where there is a definable and compelling objective involving human disease. In fact, many students are interested in reading the entire article on which this case is based. I therefore make a copy of the article available for all to read on the course website at http://www.biology.buffalo.edu/courses/bio130.
Toward the end of the case study analysis, the class is ready to extend the Alzheimer's mouse model to other areas of study. I'll ask, "Where do we go from here? Is there a better mouse model? What about treatment?" At this point I can share information on new transgenic strains of mice in which the amyloid gene has been inserted within the mouse DNA genome; as a consequence these genetically recombinant mice express biochemical, behavioral, and pathological abnormalities reminescent of Alzheimer's disease (including memory loss and amyloid plaques). On the treatment side, I also relate that vaccines containing amyloid antibodies are currently being tested for safety and effectiveness on experimental mice. Early results, which are promising, indicate that some of the biochemical and behavioral lesions associated with Alzheimer's disease are lessened.
Because this case study appears early in the second semester of the course, the class should be able to appreciate both the molecular genetic manipulations necessary to yield the transgenic mouse model and the mandated preclinical animal studies necessary to satisfy the FDA guidelines for determining therapeutic safety and effectiveness. In the first semester of the course, the class gets a heavy dose of genetics (classical and molecular) and several opportunities to implement the FDA guidelines in the search for human therapies of all kinds. Regardless of the particular disease, there is a heightened recognition at this latter stage in the course of the relevance of animal models in the pursuit of disease etiology and preclinical treatment assessment.
In my weekly freshman seminar course where we discuss various topics of contemporary biology, one of my biggest challenges was to get these first-year students to open up in class. One day I brought in this very short article on Alzheimer's along with a few questions to answer. I gave the students a short period of time to read the article and jot down a few answers. After a little coaxing, the class unexpectantly responded with enthusiasm. Before long, the students were filling up the blackboard with various ideas about what the real problem was and its broad and narrow implications.
For the past seven years I have taught a two-semester course for non-science majors, Perspectives in Human Biology. This course meets twice a week for 80 minutes each session. When the initial class size was between 40 and 70 students, I ran the case study like I did in the freshman seminar course. However, as the class size grew to more than 150, I gave the class a week to read (and analyze) the case on their own and then we discussed the case in class. Most recently, with a current class enrollment of over 300, I have made the case the subject of a written report that is due within a three-week period. In this report, I require the students to discuss (and research) in depth the four components of the scientific method evident in the mouse study. After the assignments have been turned in, I open the floor to a whole-class discussion on the case.
As a result of the success I have had using this case, I now use newspaper articles of varying length as both case study material in the classroom and subject matter for my formal exams. Daily newspapers are a virtual treasure trove of new science case study material. It's simply a matter of cutting, copying, and distributing, and then asking the important questions: "What's the problem? What did they do? What did they find? What does it mean?"
Anonymous. 1991. "Clues to Loss of Memory in Alzheimer's Reported." New York Times, 16 April, p. C10 (Associated Press).
Flood, J.F., J.E. Morley, and E. Roberts. 1991. "Amnestic Effects in Mice of Four Synthetic Peptides Homologous to Amyloid Beta Protein from Patients with Alzheimer's Disease." Proceedings of the National Academy of Sciences, USA 88:3363-3366.
Acknowledgements: Publication of this case study on the National Center for Case Study Teaching in Science website was made possible with support from The Pew Charitable Trusts.