06 - Introducing Your Students to CRISPR with Sickle Cell Gene Editing
resistant to disease, able to better withstand the weather where they grow, or produce higher crop yields. Some past projects include increasing the vitamin A content of yams in developing countries to combat eye disease and inserting human genes for the blood components used to treat hemophilia into tobacco plants. Are There Any Risks When Using CRISPR-Cas in a Living Organism? Nature’s creations aren’t formed in a laboratory, they are formed in specific environments for specific purposes and sometimes parts of that original environment are critical to their success. The sickle cell trait is a good example. Sickle cell anemia is an inherited disease caused by a mutation that produces an abnormal hemoglobin protein. The mutated hemoglobin can change the shape of red blood cells, causing them to become rigid and get caught in blood vessels. The sickle cell trait originally developed in Africa as a defense against malaria. The twisted blood cells are resistant to infection from malaria, and cyanate, a chemical found in the local guava and cas- sava plants, can help to minimize some of the difficulties from the mutated cells. When African people went to parts of the world that did not contain cyanate-rich plants, those oddly shaped red blood cells began to cause additional problems. Similarly, although initial research has been extremely successful, scientists have discovered a number of unexpected results while using CRISPR-Cas in eukaryotic organisms. For example, although CRISPR-Cas cleavage is incredibly specific, it is still possible to have off-target effects - sites in the DNA with matching sequences to the guide RNA, as well as unexpected sites that are still targeted and digested. In addition, some studies have linked CRISPR to a potential increase in cancer risk in early non-clinical tests. Therefore, additional experimentation is essential to ensure safety before each round of clinical trials. The CRISPR mechanism developed in single-celled organisms (bacteria) to fight off other single- celled organisms (viruses). It is possible that our attempts to use this system outside of bacteria is leading to some of these unexpected issues. Scientists are trying to use it in complex, multicel- lular organisms with thousands of internal wild-card variables and many more environmental variables that come into play. Basic genetics tells us that, while there are approximately 3 billion base pairs in human DNA, only about 2% of them are organized into genes that can be translated into the messenger RNA (mRNA) that tells our cells how to make proteins. The other 98% of our genome is made up of what we call non-coding DNA, and we have very limited ideas about what that does. So far we have discovered that non-coding DNA plays a role in how genes are expressed, the architecture of the chromosomes, and how we inherit specific traits as a species, but how it does these things is still unclear and there are undoubtedly other functions performed by that mysterious 98% about which we know nothing at all. When we start tinkering with the genome, we can expect surprises, and not all of them will be pleasant ones. But the only way to find out what we need to know is to begin exploring. It will take years to understand how our genome works and how each part of it affects the others, so we must pro - ceed rigorously and cautiously, a small step at a time. Fortunately, a small step at a time with no object but exploring an interesting phenomenon is a classical description of good science.
Scientists in many countries are now performing hundreds of CRISPR experiments with the diverse goals of repairing defective DNA in mice, editing genes in crops to engineer a better food supply, and rewriting the genome of the elephant to recreate a woolly mammoth. New companies using Doudna, Charpentier, and Zhang’s technologies are starting up to address everything from new cancer treatments to altering insect genomes and eliminating the mosquitoes that carry malaria. Using CRISPR as a Therapeutic for Hemoglobinopathies In this experiment, you will investigate the use of CRISPR as a therapeutic treatment for genetic diseases that affect hemoglobin, known as hemoglobinopathies. Hemoglobin, a crucial molecule in the body, is a heterotetramer composed
Figure 5: Structure of haemoglobin 1
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