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"Sickle Cell Anemia: A Fictional Reconstruction"


Debra Stamper, Department of Biology, King's College


This case was designed to be implemented in the first semester of our introductory biology course. The majority of the students enrolled in this course are freshmen majoring in either Biology or our Pre-Physician Assistant Program. Each week, students attend three 50-minute lectures and one 50-minute problem hour. Most of the sections of the case were presented during the problem hour (although one section was done at the conclusion of a lecture period). The different parts of this case all relate to various aspects of sickle cell anemia. In Part I, students are introduced to some of the key investigators responsible for determining the molecular basis of the disease. In Parts II, III, and IV, students learn about the functioning of erythrocytes and are introduced to the notion that changes in the environment can influence the functioning of cells. Part V allows students to become familiar with the process of osmosis and how it can influence the sickling of the erythrocytes. Throughout the case, students must address experimental design questions.

be doing gel electrophoresis later in the semester, and 2) some of the students are already familiar with this technique. The electrophoresis results are drawn in their correct relative position, but these specific samples are a creation of the author. Irving Sherman's experiences at Boston are completely fabricated. I have no knowledge that he ever lived in the Boston area. All graduate students mentioned are also fictional, as is the intern and patient described at the end of Part V.


Unless otherwise noted below, students were divided into cooperative learning groups. Each group consisted of three to four students. The groups were pre-assigned by the instructor at the beginning of the semester and remained intact until the conclusion of the course. The students were told that it would be highly beneficial to bring both their textbook (5th edition of Biology by Campbell et al.) and their lecture notes to the problem hours. Students were occasionally given supplemental material (such as overhead transparencies) with some of the sections of the case. Although the supplemental material is a nice addition, it is not required for successful completion of this case. Many introductory textbooks discuss some aspect of sickle cell anemia.

Fact or Fiction

This case is a work of fiction that refers to real events and people. All of the discoveries mentioned were made by the individuals they are attributed to, as were the observations made by Dr. Vernon Hahn. The time between discoveries has been dramatically condensed, however. It is true that William Castle knew of Irving Sherman's spectrophotometric observations of sickled cells, but the letter written in this case is fiction. Both Linus Pauling and William Castle were members of the same medical advisory committee and it has been reported that they discussed sickle cell anemia on a train; however, their conversation as presented in this case is fictionalized. The initial separation of HbA and HbS was done using a different technique than that presented in the case. I elected to present it as gel electrophoresis for two reasons: 1) students enrolled in the course will

Part I ­ The Inquiry Begins

Learning Objectives for Part I After completing Part I, students will be able to: · identify pieces of experimental evidence; · determine whether one piece of experimental evidence supports another piece; · determine the need for "blind" tests; · recognize how the side groups of amino acids can influence the overall charge of a protein; · recognize the interdependence of the different levels of protein structure; and · recognize the need to address a problem from different angles (or using different techniques).

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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE Presentation of Part I Prior to this material being presented, students have had lectures on the scientific method, inorganic chemistry, and organic chemistry. They have had no lectures on cellular components and have not been instructed about any aspect of sickle cell anemia. This part of the case can be completed in a 50-minute period. Students read the section individually. They are instructed to circle any words and/or phrases that they do not understand. After reading the material, they then assemble into their cooperative learning groups. As a group, they are asked to list all the experimental evidence that relates to sickle cell anemia, including why each piece of evidence is a significant finding. They then answer the questions posed at the end of the section. Their textbook contains a diagram of the molecular structure of the different amino acids (see Biology by Campbell, 5th ed., Figure 5.15, p. 69) which aids in answering the questions. While the students were working, I moved around to the different groups. To initiate a conversation with each group I asked them if they would like me to clarify one of the terms they had circled. Since most of the students have not performed electrophoresis, this tends to be the most common explanation requested. For the groups that did not request electrophoresis to be explained, I asked them to explain the technique to me, filling in or modifying their explanation as needed. I discovered that many groups had no idea where to start to answer the question relating the electrophoresis data with the data from Vernon Ingram. For these groups, I simply redirected their attention to the molecular structure of the different amino acids. This was sufficient for most of the groups that were stuck, although they still had a difficult time realizing that I wasn't going to point to a section in the textbook that simply spelled out the answer. After a few minutes of grumbling about the need to do their own thinking, they would finally figure it out. At the end of the class, each group turned in a list of experimental evidence and answers to the questions. (See below for an Answer Key that provides suggested answers to these quesitions.) · assimilate and apply material presented in lecture and/or the textbook to a novel question; · understand the role of the nucleus and plasma membrane in the normal functioning of a cell; · understand the proper use of a control for an experiment; and · recognize that changing the environment in a cell can alter the functioning of the cell. Presentation of Parts II, III, and IV Prior to being presented with this section, students had been given lectures on the various organelles found within a cell and the structure of the plasma membrane. They had not received the lectures on membrane transport. They were directed to a photo in their textbook (see Biology by Campbell, 5th edition, Figure 5.19, p. 72) comparing the microscopic appearance of red blood cells from a normal individual and those from an individual with sickle cell anemia. They were also shown an overhead transparency of a photo of normal red blood cells passing through a capillary (from Understanding Sickle Cell Disease by M. Bloom, Figure 3.1, p. 40). This photo depicts the red blood cells passing through a capillary in single-file, bending into a bullet shape in order to "squeeze" through. This section is broken down into three distinctive parts. The students receive Parts II and III in one class and Part IV the next. Students must finish Part II prior to receiving Part III. Many of the groups required the entire 50 minutes to complete Part II. Because Part II took so long to complete, Part III was given to the students as homework to do either individually or as a group. A couple of the groups were able to complete both Parts II and III during the 50-minute period. The vast majority of the students who completed Part III outside the class period worked in their cooperative learning groups. Only four of the 31 students in the class elected to work independently; at least two of these students had outside commitments that hindered their ability to meet with other students outside of class. Most of the students had difficulty initially addressing the questions in Part II. This was related to their expectation that the answers to the questions would simply be found in the textbook. Most groups were able to generate limitations for cells without a nucleus, but had a harder time coming up with any benefits. I talked to the groups who had difficulty with this a little more about the developmental process that erythrocytes undergo. Often I commented that since the cells lose the

Part II ­ Normal Functioning, Part III ­ Starting at the Bottom, and Part IV ­ Ghosts

Learning Objectives for Parts II, III, and IV After completing this section of the case, students will be able to:

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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE nucleus just prior to entering the plasma, that this may enhance their functioning in the plasma. If that didn't work, I redirected their attention to the overhead (which was displayed throughout the entire period). Part IV was done separately during the last 15 minutes of a lecture period. It was during this section of the case that many of the students realized that they could answer the question being posed, even if the answer wasn't given in the textbook (see Answer Key). interested in seeing if the students could continue on their own. Following the lectures on genetics, I included the following question on their lecture exam: Sickle cell anemia occurs in individuals who are homozygous recessive. Individuals who are either homozygous dominant or heterozygous do not have the disease. Heterozygous individuals are said to have sickle cell trait since they are carriers. These carriers usually show no ill effects during their lifetime. However, if they find themselves in a situation where oxygen is limited (such as at high altitude), some of their red blood cells may show signs of sickling. Is this an example of complete dominance, codominance, or incomplete dominance? Provide a basis for your choice. In their answer I expect to see something along the lines that since the phenotype of the heterozygous condition is not exactly like either of the homozygous conditions, then it should be an example of codominance. I also had a section on their final exam (which is a comprehensive exam) that addressed different aspects of sickle cell anemia. For this exam, I give them a number of study questions which I draw upon to write the exam. Below are the study questions that I gave the class to coincide with this case. During the final exam, students are given a copy of the genetic code.

Part V ­ Throwing Water at the Problem

Learning Objectives for Part V After completing this section of the case, students will be able to: · determine the osmolarity and tonicity of different solutions; · predict the movement of water when cells are placed into solutions of different tonicity; · understand how the process of osmosis can alter the concentration of intracellular molecules; · understand that more than one variable may affect the sickling rate of red blood cells; · apply their knowledge of osmosis to a clinical problem; and · predict possible side-effects of treating a patient with solutions of different tonicity. Presentation of Part V This part of the case is presented to the students after the lectures on membrane transport. It is given to the students to work on in their cooperative learning groups during a 50-minute problem hour. They are instructed that in order to complete the second half of the section (the clinical problem), they must first be able to answer questions 1 through 6. At the end of the period, each group turns in their answers to the questions (see Answer Key). Areas in which students needed some additional guidance included determining which molecules dissociate in water and how changes in the volume of water contained within the plasma membrane of a cell can alter the concentration of intracellular molecules (such as hemoglobin).

Study Questions

Sickle cell anemia is the expression of a recessive allele for a gene (which follows Mendelian genetics). Individuals who are heterozygous for this gene have the sickle cell trait. 1. In normal individuals the sixth amino acid of hemoglobin is encoded by the codon "GAG," whereas in individuals with the recessive allele the sixth amino acid is encoded by the codon "GUG." What difference will this make in the primary structure of the protein? 2. This change in the primary structure of the protein will end up making changes in the 3-D structure of the hemoglobin protein. Be able to describe all levels of protein structure, from primary to quarternary. 3. Be able to determine the genotype of different individuals based upon whether they are normal, have sickle cell trait, or have sickle cell anemia. Use the letter "A" for this gene. 4. Be able to use a Punnett Square to make genetic predictions on the mating outcomes of different individuals. Be able to do this for when you are interested in just the hemoglobin gene or when you are interested in 2 different genes (such as


Genetics Problems

Since sickle cell anemia is a heritable trait, it is easy to continue this case into the genetics component of the class. Instead of writing another section to the case, I was

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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE the hemoglobin gene and a gene on a different chromosome that encodes for the ability to curl your tongue). 5. Describe why the inheritance of the gene for the beta subunit of hemoglobin is an example of incomplete dominance. 6. Be able to make comparisons between a normal individual, someone with the sickle cell trait, and a person with sickle cell anemia in terms of the concentration of HbA and HbS in their red blood cells. How would these differences influence the rate at which their red blood cells would sickle? For all of the genetics problems given to the students, the assessment of their performance was done on an individual basis. Problems 1. Determine the primary amino acid sequence of the initial portion of the beta subunit in HbA. Answer: Val - His - Leu - Thr - Pro - Glu - Lys 2. Determine which nucleotide is different in the mRNA for the beta subunit in HbS. Answer: the 17th nucleotide is uracil.


Answers to the questions posed in the case study are provided in a separate answer key to the case. Those answers are password-protected. To access the answers for this case, go to the key. You will be prompted for a username and password. If you have not yet registered with us, you can see whether you are eligible for an account by reviewing our password policy and then apply online or write to [email protected]

Protein Synthesis Problem

After the lecture on translation, I gave the students the following problem set to complete during a 50-minute problem hour. Students were directed to the page in their textbook that contained the genetic code (Biology by Campbell, 5th edition, Figure 17.4, p. 299). They worked on this problem in their cooperative learning groups. At the end of the problem hour, each group turned in their answers to the questions posed. Translation of Hemoglobin (the continuation of the sickle cell saga) Hemoglobin is a large protein molecule that consists of four subunits (2 alpha chains and 2 beta chains). Hemoglobin is synthesized within red blood cells and functions to reversibly bind oxygen molecules. The alpha and beta chains are products of two separate genes found on different chromosomes. Individuals that have sickle cell anemia have two copies of a "mutated" form of the gene that encodes for the beta subunit. This form differs from the original in only 1 nucleotide. This nucleotide difference results in a different amino acid placed in the sixth position of the protein (the mutated gene encodes for a valine residue instead of the glutamic acid encoded for by the normal gene). The protein encoded by the normal gene is designated HbA while the protein found in individuals with sickle cell anemia is HbS. Below is the initial nucleotide sequence found in the mRNA for the beta subunit of HbA. G U G C A C C U G A C U C C U G A G A A G (etc.)


Books and Articles

Bloom, Miriam. Understanding Sickle Cell Disease. Jackson: University Press of Mississippi, 1995. Campbell, N.A., J.B. Reece, and L.G. Mitchell. Biology, 5th ed. Menlo Park, Calif.: Benjamin Cummings, 1999. Edelstein, Stuart J. The Sickled Cell, From Myth to Molecules. Cambridge: Harvard University Press, 1986. Reid, C.D., S. Charache, and B. Lubin (eds.). Management and Therapy of Sickle Cell Disease, 3rd ed. Bethesda: National Institutes of Health; National Heart, Lung, and Blood Institute. NIH Publication #96-2117, 1995. Strasser, Bruno J. 1999. Sickle Cell Anemia: a Molecular Disease. Science 286: 1488­1490. Stryer, Lubert. Biochemistry, 2nd ed. San Francisco: W.H. Freeman & Company, 1981, 57­102. Todd, James Campbell, and Arthur Hawley Sanford. Clinical Diagnosis by Laboratory Methods, 14th ed. Edited by I. Davidson and J.B. Henry. Philadelphia: W.B. Saunders Company, 1969, 227­237.

Web Sites

Joint Center for Sickle Cell and Thalassemic Disorders. A site that provides information on many different aspects of hemoglobin, sickle cell disease and current treatments.

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NATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCE "New Hope for People with Sickle Cell Anemia." Revised edition of article by same title by Eleanor Mayfield which originally appeared in the May 1996 FDA Consumer. [Editor's Note on Feb. 15, 2010: Link was current at the time the case was originally developed.] Sickle Cell Information Center. Another good overall source with information for both the layperson and the clinician. Sickle Cell Syndromes. php?mid=6264. A site with information on a more clinical level.

· Acknowledgements: This case was developed as part of a National Science Foundation-sponsored Case Studies in Science Workshop held at the State University of New York at Buffalo on June 7­11, 1999 (NSF Award #9752799). Copyright held by the National Center for Case Study Teaching in Science, University at Buffalo, State University of New York. Originally published September 14, 2000; last updated February 15, 2010. Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work.

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