BioInteractive’s Sickle Cell Resources: From Gene Therapy to Evolution
My students are often interested in knowing more about sickle cell disease. This year, athletes in my class were particularly interested in knowing why certain football players suffered more severe symptoms from their sickle cell trait when competing in higher-altitude environments, such as Denver.
It is rare for a single phenomenon to span such a large range of concepts, but BioInteractive has so many resources on sickle cell disease that I use this topic to discuss the central dogma, gene therapy, Mendelian genetics, and evolution.
While many of my colleagues begin this unit with evolution and the link between malaria and sickle cell disease, I like to start with the sickle cell mutation and continuously tie the lesson back to the genetic basis of the sickle cell trait. You may have used the “‘Fixing’ Gene Expression” card-sort activity to cover the central dogma, which provides students with “snapshots” of the processes of replication, transcription, and translation that they label and put in the correct order. To delve deeper into how this protein mutation affects the shape of the cells, the "How Do Fibers Form" activity guides students through building models of hemoglobin molecules with paper to visualize how a specific amino acid substitution (valine to glutamic acid) causes hemoglobin molecules to form elongated fibers. Students see that these fibers distort the shape of the red blood cell, causing the cell to sickle. Sickled cells are elongated and can get trapped in small capillaries, causing debilitating pain. This activity also discusses the biochemical mechanism of why sickling occurs in low-oxygen conditions and provides a great lead-in to a discussion of the symptoms of sickle cell disease. If this level of detail is too much for your class, you may consider using this one-minute video to summarize the sickling process instead.
As sickle cell disease is a condition of the blood and its genetic basis is (relatively) well-characterized, gene therapy treatments using CRISPR-Cas9 technology are currently in clinical trials in the United States. The treatment involves turning on fetal hemoglobin gene expression by disrupting its repressor in hematopoietic stem cells from the bone marrow. Interestingly, people with the sickle cell mutation and this repressor mutation do not experience the usual symptoms of sickle cell disease. This treatment is discussed as a case study in the Central Dogma and Genetic Medicine Click & Learn. Students can then explore the process of gene editing with the CRISPR-Cas9 Mechanism & Applications Click & Learn and discuss why fetal hemoglobin, rather than adult hemoglobin, was chosen as the target for this therapy.
Now that the students have a handle on the genetic basis of sickle cell disease, we can ask about how it is inherited. The “Mendelian Genetics, Probability, Pedigree, and Chi-Square Statistics” activity begins with Punnett squares and the relationship between genotype and phenotype. When teaching about sickle cell disease, it is particularly important to discuss individuals who are both homozygous and heterozygous, as those who are heterozygous often still have symptoms under certain conditions, such as in low oxygen levels. This distinction is also important when discussing malaria resistance later in the lesson. From these Punnett squares, students are able to predict probabilities and pedigrees for families that carry these mutations. From there, students investigate a larger group of individuals and use chi-square tests and calculate P values for sickle cell inheritance. This activity is a great opportunity to hone quantitative skills while covering basic genetics concepts.
If we look beyond pedigrees to a population level, we find there are certain areas of the world in which the sickle cell trait is more prevalent. The video The Making of the Fittest: Natural Selection in Humans and accompanying resources provide evidence for human evolution, driving home the point that mutations are random; in some conditions they may be detrimental and in others they may be beneficial. This video is also a great example of the process of science, as it shows research taking place over many years with many collaborators. The related activity “Sickle Cell Disease and Malaria: A Lesson on the Nature of Science” highlights the breakthroughs required to make the link between sickle cell and malaria. The activity “Sickle Cell Disease and Malaria: Testing a Hypothesis” discusses the process of using observations and research questions to generate a testable hypothesis. Finally, the genetics and evolution concepts are tied together in the “Population Genetics, Selection, and Evolution” activity, in which students calculate the frequency of the sickle cell trait in a population using Hardy-Weinberg equations.
Although the malaria and sickle cell story is a compelling example of human evolution, it is important to address a common misconception about race and sickle cell disease in your class. Students may have the misconception that sickle cell disease is found only in people of African descent. As most of the early research, including what was showcased in the BioInteractive videos, was performed in Africa, it is essential for students to understand that the sickle cell trait is selected for in areas where malaria is prevalent, which includes certain regions of Africa and other areas of the world as well. The sickle cell mutation is not tied to race, since race is not a biological construct but a sociological one. While the BioInteractive team is working to revise and update many of these resources to address this misconception, an additional set of resources that can help with this distinction is the video The Biology of Skin Color and its related resources, which lead students through how skin color is genetically and physiologically determined.
At the end of these lessons, my students were able to answer their own question about why athletes with the sickle cell trait tend to have more symptoms when competing in Denver. They have seen how the genetic mutation for sickle cell causes a valine-to–glutamic acid substitution and how that substitution causes deoxygenated hemoglobin molecules to form fibers. These fibers cause the red blood cells to be sickle-shaped. While these sickled cells are prevalent in homozygous individuals, for those who are heterozygous (carry the sickle cell trait), low-oxygen conditions (like with strenuous exercise at high altitudes) often trigger the fiber formation, sickling of cells, and the resulting capillary blockage and pain.
There are a lot of resources on this topic! To manage them, I would recommend setting up a BioInteractive account and using the Resource Playlist function. It allows you to select resources, write notes to yourself about them, and put them in an order that works for your course. I’ve put together a Resource Playlist for all the resources mentioned here, in the order in which they have been implemented in my course, that you’re welcome to use as well!
Holly Basta is in her sixth year of teaching (and waiting on her tenure decision!) at Rocky Mountain College, a small liberal arts college in Billings, Montana. She teaches nonmajors biology, virology, immunology, cancer biology, and physiology.
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