In the Classroom edited by
Teaching with Problems and Case Studies
Grant R. Krow
Thalidomide Makes a Comeback: A Case Discussion Exercise That Integrates Biochemistry and Organic Chemistry
Temple University Philadelphia, PA 19122
Kim Kostka University of Wisconsin–Rock County Janesville, WI 53546
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Nicole Bennett Department of Chemistry, Hope College, Holland, MI 49422 Kathleen Cornely* Department of Chemistry, Providence College, Providence, RI 02918-0001;
[email protected] Background In its Spring 1998 Newsletter the American Chemical Society Committee on Professional Training (CPT) announced that “all ACS-approved curricula in chemistry shall be required to include the equivalent of three semester credit hours of biochemistry” as an advanced class or as part of the chemistry core curriculum by the year 2001 (1). Chemistry departments that choose the first option may decide to develop new onesemester biochemistry courses. Choosing the second option would involve integrating biochemistry into general, organic, analytical, and physical chemistry courses where appropriate. The case discussion method, which involves teaching scientific theory in a framework that students can relate to their own world (2), is an interdisciplinary pedagogical tool. Therefore, this method can be used to address either option. The case is a fact-based, fictional story in which an FDA official must decide whether to carry out the agency’s threat to shut down several buyers clubs that import thalidomide from overseas and dispense it to their members for the treatment of mouth ulcers and muscle wasting associated with AIDS. Thalidomide was banned worldwide in the early 1960s after its use was linked to birth defects in babies whose mothers had taken the drug to alleviate morning sickness. The drug had not been approved in the United States in 1995 (the year the case study is set) but AIDS activists and others were pressuring the FDA to approve it, since in recent clinical trials thalidomide had shown promise in the treatment of HIVrelated diseases and cancer. The viewpoints of scientists and nonscientists affected by this issue are represented. Facilitating the Case Students are required to read the body of the case, analyze data, and search for information using limited leads. Using well-considered arguments based on their research, they are asked to come to conclusions about how the element of risk involved in thalidomide distribution is assessed, how thalidomide acts on the body, and how its analogs should be designed. The number of class periods allotted to case discussion may be flexible, but should be a minimum of two days. After reading the case, the students may view a videotape of the 60 Minutes report on thalidomide broadcast on July 28, 1996.1 They are then divided into the three interest groups described below. Scientific Consultants to the Thalidomide Victims. Students in this group are asked to serve as consultants to the Thali-
domide Victims Association of Canada, an advocacy group that raises money for the costly hospital bills of surviving thalidomide victims (3). The members of the association are dismayed that the drug is being marketed by the Celgene Corporation and that approval for its use is under consideration by the FDA. The association has learned that Celgene is considering marketing the drug as a racemic mixture, and members are concerned that one of the enantiomers is particularly teratogenic. The students assigned to this group are asked to evaluate scientific data by two research groups who attempted to address the question of specific enantiomeric toxicity (4). After they have analyzed the data, they are asked to issue a recommendation to the Thalidomide Victims Association that will assist the members in formulating their position on this issue. Medical Research Group. In 1991, Gilla Kaplan and her associates at the Rockefeller University discovered that thalidomide has the ability to inhibit the production of tumor necrosis factor α (TNF-α) from HIV-infected cells. TNF-α is the causative agent that induces the fever, malaise, muscle weakness, and body wasting experienced by HIV-infected individuals. TNF-α also has the ability to act as an agonist to stimulate latent HIV-infected cells to become productive (5). The students assigned to this interest group carry out a critical analysis of Kaplan’s scientific data and make conclusions concerning thalidomide’s effectiveness as a TNF-α inhibitor in vitro and in vivo. Drug Design Group. Scientists at Celgene Corporation, the company that markets thalidomide, have begun developing thalidomide analogs, compounds that are as biologically potent as thalidomide (or more so) but lack the teratogenic side effects. Students assigned to this group are given structures of several thalidomide analogs developed by George Muller at Celgene (6 ). These analogs have not yet been marketed, but are expected to be available for clinical trials soon. Given experimental data that indicates the ability of each analog to act as an inhibitor of TNF-α, students discern which aspects of the chemical structure of the analogs are responsible for the observed biological activity. They are also asked to design their own thalidomide analogs based on the data provided. Further information regarding the interest groups and a list of questions for each group are provided in the appendices to the case in the supplemental material online.W Students are allowed a sufficient amount of time to answer the assigned questions during class or outside of class. Each group presents a brief report of its findings to the rest of the class; then
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In the Classroom
the entire class discusses the case. Finally, each group comes up with a plan for the appropriate action the FDA official should take. The case can be used at the end of a second-semester organic chemistry course or in an introductory biochemistry course. Students who undertake this case study must have an understanding of the mechanism of amide hydrolysis. They should be familiar with stereochemistry and should be able to identify stereogenic carbons and assign absolute configurations using the Cahn–Ingold–Prelog R–S system of nomenclature. Carrying out the case study exercise will further students’ understanding of chiral molecules, which is important in organic and biochemistry. Students should also have some understanding of the biological role of nucleic acids, and it is likely that the depth of understanding among sophomore organic students on this topic will vary. Students majoring in chemistry may not have studied nucleic acids since high school biology, whereas biology majors will have taken an introductory biology course and may even have had genetics. Organic chemistry instructors may wish to ensure that their courses include a discussion of the structure and function of nucleic acids. Biochemistry instructors who wish to use the case study in their courses should cover nucleic acids early in the semester. Students should understand the central dogma of molecular biology (DNA makes RNA makes protein), but their understanding need not include the detailed mechanisms normally covered at the end of a biochemistry course. Scheduling At Hope College, the case learning exercise was carried out during the last week of class in two sections of the second-semester organic chemistry course taught by different instructors. The students were given a copy of the case on the Friday before the last week of class and asked to write a paragraph describing what they believed the FDA official should do. On the following Monday the class watched the 60 Minutes report on thalidomide and then divided into groups of four or five to discuss their paragraphs. A spokesperson for the group then gave a synopsis of the group’s opinion. If there was a lack of consensus, opposing opinions were outlined. Each group was then given the three appendices to the case. Students were asked to read all of them for homework, but were responsible for answering the questions at the end of only one. On Wednesday the students discussed their individual answers with the members of their group. On Friday representatives from each group presented answers to the questions (or selected questions, in the case of multiple groups, to avoid redundancy in presentation). At Providence College, the case was assigned for the last week of class in the introductory biochemistry course. The students were given a copy of the case on the Friday before the last week and assigned to a group. They were required to meet with their group outside of class to answer the questions and to prepare a class presentation. The following Friday was devoted to class presentations and discussion of the case. One class period might be sufficient for a small class, but two class periods are required for a larger class.
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Assessment Students may be assessed regarding their ability to work in groups, to critically analyze scientific data, and to develop public policies based on risk–benefit analysis. There are a variety of strategies that can be used to accomplish this. Students may be evaluated either individually or as a group on their written and oral presentations of the answers to the assigned questions. Instructors may wish to grade students individually on their participation in class discussion of the case. Requiring students to answer essay questions about the case on exams is another method of individual evaluation. When surveyed, Hope College organic chemistry students expressed a preference for being graded individually. Providence College biochemistry students preferred being graded as a group; however these students had spent the entire semester working on case studies and were accustomed to group evaluation. Student Responses When asked to rate how well the case helped them to understand how organic chemistry and biochemistry could be applied to real problems, 20% of Hope College students responded that the case worked very well, 67% thought that it worked well, and 12% thought that the case was adequate. When asked how well the case helped them to understand the social issues surrounding drug distribution, 48% responded that the case worked very well, 48% that it worked well, and 4% that it was adequate. Formal surveys were not conducted at Providence College, but informal discussions with the students after the case-study exercise indicated that they were interested in the case study and found the topic compelling; the amount of time spent working outside of class on the case reflected this. Summary The interdisciplinary case study exercise presented here integrates concepts covered in organic chemistry and biochemistry courses and can be used in either course to fulfill the ACS CPT guidelines for including biochemistry topics in the curriculum. The case involves a real-world problem that requires students to analyze and interpret actual qualitative and quantitative scientific data. Students use higher-order thinking skills as they analyze data that are often ambiguous, conflicting, and difficult to interpret. The case addresses social as well as scientific issues. Acknowledgments We wish to acknowledge the following people and organizations who contributed to the success of this case study: The Pew Midstates Consortium, for sponsoring our attendance at the Case Study Symposium at St. Olaf College; Anne Walter of St. Olaf College, for helpful suggestions; the Hope College and Providence College Chemistry Departments; Rodney Boyer and Elizabeth Sanford of Hope College; Kenneth Overly of Providence College; and Kurt Fromke. We would also like to thank the reviewers whose comments resulted in the improvement of our manuscript.
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Supplemental Material
The following supplemental material for this Contemporary Problems and Case Studies (CP/CS) exercise can be found in this issue of JCE Online: (i) a CP/CS summary; (ii) the full CP/CS; (iii) appendices to the CP/CS; (iv) instructions on how to facilitate the case, including questions to be answered by students outside of class and questions to facilitate class discussion; (v) analysis of key subjects including background and history and answers to the questions; and (vi) a list of useful references. Note 1. This video can be ordered by calling 60 Minutes at 800/ 848-3256.
Literature Cited 1. Report of the Committee on Professional Training of the American Chemical Society; CPT Newslett. 1998, 2 (3), 1. 2. Krow, G. R.; Krow, J. B. J. Chem. Educ. 1998, 75, 1583–1584. Cornely, K. J. Chem. Educ. 1998, 75, 475–478. 3. Stolberg, S. G. Their Devil’s Advocates; The New York Times Magazine, Jan 25, 1998, p 20. 4. Fabro, S.; Smith, R. L.; Williams, R. T. Nature 1967, 215, 296. Eriksson, T.; Björkman, S.; Roth, B.; Fyge, Å.; Höglund, P. Chirality 1995, 7, 44–52. 5. Makonkawkeyoon, S.; Limson-Pobre, R. N. R.; Moreira, A. L.; Schauf, V.; Kaplan, G. Proc. Natl. Acad. Sci. USA 1993, 90, 5974–5978. 6. Muller, G. W. Chemtech 1997, 21–25.
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