Sickle Cell Anemia: Videos & Practice Problems

Sickle cell anemia results from a homozygous point mutation in the beta subunit of hemoglobin, altering glutamate to valine at the 6th position. This mutation leads to the hydrophobic effect, causing mutated hemoglobin to agglutinate and deform red blood cells into a sickle shape. These sickled cells can obstruct blood flow, leading to organ damage and anemia. Interestingly, heterozygous individuals possess resistance to malaria, illustrating a natural selection advantage in malaria-endemic regions despite the health risks associated with sickle cell disease.

Sickle Cell Anemia

In this video, we're going to begin our discussion on sickle cell anemia. So most of you guys have probably heard of sickle cell anemia before in your previous biology courses. Recall that sickle cell anemia is a disease that is due to a hemoglobin mutation. This hemoglobin mutation causes the red blood cells to take on a sickle shape that ultimately causes health issues. We'll talk more about these health issues a little later in our course. Recall that the term anemia is just referring to a low number of erythrocytes or a low number of red blood cells in patients with sickle cell anemia. Again, sickle cell anemia disease is due to a hemoglobin mutation, and more specifically, it is due to a homozygous point mutation in the DNA for the gene that codes for the beta subunit of hemoglobin, ultimately changing the amino acid residue at the sixth position of the beta subunit from a glutamate residue to a valine amino acid residue. This 6 here after the three-letter codes is just referring to the fact that it is the amino acid residue at the sixth position of the beta subunit that is being affected.

We can see this demonstrated in our image, where, on the top half of our image, we have the normal conditions, and on the bottom half, we have the conditions that cause sickle cell anemia. Notice that the DNA is being shown here for normal conditions, and through transcription, we are able to get an RNA molecule. Through translation, we are able to get our amino acid chain. Notice that at the sixth position specifically, we would have a glutamate amino acid residue under normal conditions, which would lead to normal protein folding and result in the normal hemoglobin molecule, which we would refer to as HBA under normal conditions to indicate it is the normal adult hemoglobin.

With sickle cell anemia, notice that it is due to a single homozygous point mutation in both copies of the gene that codes for the beta subunit of hemoglobin. Down below here, notice that there is just a flip-flop of the A and the T from up above. This single point mutation leads to all the complications caused by sickle cell anemia. Through transcription, we get a different RNA molecule and instead of having an A in the center nucleotide here, we would actually have a U, in the RNA because remember that Ts are replaced by Us in RNA. Through translation, notice that, instead of getting a glutamate residue, if we were to use the genetic code and this RNA code, we would actually get a valine amino acid residue at the sixth position. Recall that glutamate has a negative charge on it, whereas valine is a neutral amino acid residue. This neutrality alters the protein folding. Notice this little nudge coming out represents the mutated hemoglobin with altered protein folding. The mutated hemoglobin we are going to refer to as HBS for the hemoglobin that causes sickle cell anemia. It is important to note that all the complications of sickle cell anemia are due to just this one swap of the nucleotides. This one mistake leads to all the sickle cell complications, which is incredible to think about how we can get diseases through such a small change in our DNA.

We'll be able to talk more details about sickle cell anemia as we move forward in our course. I'll see you guys in our next video.

Sickle Cell Anemia

So now that we've refreshed our memories that sickle cell anemia is the result of a homozygous point mutation, in this video we're going to talk about how the agglutination of the mutated hemoglobin molecules actually causes sickle cell anemia. And so the mutation from our previous lesson video actually leads to the agglutination, which is really just a fancy word for the clumping of these mutated hemoglobin chains due to the hydrophobic effect. And so, notice down below, we're showing you guys these mutated hemoglobin molecules. And of course, these little pink protrusions here represent the mutated amino acid residue, which is a valine residue in the mutated hemoglobin. And recall that valine is a non-polar amino acid, and non-polar molecules can form interactions with each other via the hydrophobic effect. And so, notice that we have these hemoglobin molecules clumping together, essentially agglutinating, and they can actually create these long chains of mutated hemoglobins. Ultimately, these mutated hemoglobin chains can result in the sickle cell anemia shape. And so, fortunately, hemoglobin's oxygen affinity and allosteric properties are unaffected even in this mutated hemoglobin. However, the mutated hemoglobin chains here, or aggregates, can deform the red blood cell, causing this sickle cell shape that we see here. And so, notice that we have the sickle cell shape right next to a normal red blood cell here so that you can compare the shapes. And really, it's the shape of the sickle cell red blood cell here that is going to cause most of the health complications associated with sickle cell anemia. And so down below, right here, we can say that the mutated hemoglobin clumps and causes sickle cell anemia. Now that we can better understand exactly how mutated hemoglobin molecules can lead to a sickle cell shape, in our next video, we'll be able to talk about the exact complications that these sickle cells can cause health-wise. So I'll see you guys in that video.

The amino acid substitution of Val for Glu in Hemoglobin S (sickle-cell hemoglobin) is problematic because it substitutes a _________________ amino acid residue with a _________________ amino acid residue.

• A. Polar ; nonpolar.
• B. hydrophobic ; charged.
• C. Aromatic ; Polar.
• D. Nonpolar ; aromatic.

Answer: (B)

In sickle cell anemia, the molecular basis of the malfunction of the hemoglobin molecule is:

• A. Faulty binding of iron by the heme groups.
• B. Insufficient iron in the diet.
• C. Substitution of a single amino acid in the DNA sequence.
• D. Reduced affinity for oxygen.
• E. Silent mutation in the DNA sequence causing a single amino acid substitution.
• F. Point mutation in the DNA sequence causing a single amino acid substitution.

Answer: (F)

Sickle Cell Anemia

In this video, we're going to talk about the physiological effects of sickle cell anemia. So the sickled red blood cells are actually more susceptible to becoming trapped in small blood vessels, and if the sickled red blood cells do become trapped in these small blood vessels, that can impair blood circulation throughout the body. Impaired blood circulation can cause organ damage. Also, the sickled red blood cells are more susceptible to rupturing, and so they rupture a lot more easily than normal red blood cells, leading to anemia, which is again a low red blood cell count.

And so, down below in our example, we can see the sickle cell anemia physiological effects. Notice that we're showing you the normal red blood cells as these circles and the sickle-shaped red blood cells as this sickle shape. Notice that the normal red blood cell will have a normal red blood cell count and there's going to be proper flow through small blood vessels. However, notice that with sickle cell anemia, there's going to be quite a low red blood cell count, essentially anemia, due to the fact that, again, the sickled red blood cells can rupture more easily. But there's also the chance for impaired circulation, which is also referred to as occlusion. Occlusion is just this idea of the blockage of blood vessels. Of course, that is going to lead to organ damage and can cause many different health complications.

So even though sickle cell anemia is mainly associated with health complications, in some scenarios, in some populations in the world, sickle cell anemia can actually be a beneficial thing to a population. We'll be able to talk about that more in our next video. So, I'll see you guys in that video.

Sickle Cell Anemia

In this video, we're going to talk about how sickle cell anemia can actually provide resistance to malaria. And so recall from our previous lesson videos, we said that sickle cell anemia was caused by a homozygous point mutation. Meaning, that both copies of the gene were mutated. However, heterozygous individuals for the sickle cell trait, meaning that they only have one copy of the gene that's mutated, actually have resistance to malaria but they do not have sickle cell health issues. And so, heterozygous sickle cell trait, because they have resistance to malaria and do not have sickle cell health issues, are actually selected for by natural selection in areas of the world with a high prevalence of malaria. Now, the exact mechanism of malaria resistance is not yet fully understood. So we're not going to talk about this in our course.

Now, notice down below in our image on the left-hand side, the normal allele or the normal version of the gene for hemoglobin is represented by a capital A. And then, of course, the sickle cell allele or the mutated version of the gene for hemoglobin is represented by a lowercase a bolded and in red like this. And so a homozygous normal individual would have 2 copies of the normal allele and so they are going to have normal red blood cells like what we see here. And so they are not going to have sickle cell disease. However, they're going to be fully susceptible to malaria. And so, in an area of the world with a high prevalence of malaria, being homozygous normal is actually not going to be beneficial, because it is susceptible to malaria and again that is going to cause complications.

Now, on the other hand, homozygous mutant individuals, which have 2 copies of the sickle cell allele, are obviously going to have severe sickle cell disease just like what we can see in this image. Their cells are going to be sickle shaped. However, even though they do have severe sickle cell disease, they are going to have resistance to malaria. And so, resistance to malaria is going to be good in an area of the world that has a high prevalence of malaria, but having severe sickle cell disease is still not a good thing. So, this is not beneficial at all. However, a heterozygous individual would have one copy of the normal allele and one copy of the sickle cell allele, would only have mild sickle cell disease or not have sickle cell health issues at all. And they do still have resistance to malaria. And so, this, a heterozygous individual, is actually going to be beneficial in an area of the world that has a high prevalence of malaria. And so this would be preferred in an area of the world with a lot of malaria.

And so over here on the right, what we have is a little image to help you guys see how this little structure right here represents the parasite that causes malaria and it infects red blood cells. And so you can see that this parasite that causes malaria is saying, "This looks like a healthy cell I can infect." And so, the malaria parasite will infect normal healthy red blood cells. However, over here, you can see we have the sickle cell, and it says, "I'll get nowhere if I infect this cell, right here." And so, notice, that being heterozygous for the sickle cell trait, you do have some sickle cell shaped blood cells and that is going to help provide at least some resistance to malaria more so than if you had all normal red blood cells. And so, this here concludes our lesson on how malaria resistance is related to sickle cell anemia, and, we'll be able to get some practice utilizing these concepts that we've learned in our next few videos. So, I'll see you guys there.

Match the following key terms with their appropriate image (A or B):

a) HbS: Image _____
b) HbA: Image _____
c) Malaria resistance: Image _____
d) Heterozygous (Aa): Image _____
e) Homozygous (AA): Image _____
f) Low RBC count: Image _____
g) RNA sequence GAG: Image _____
h) RNA sequence GUG: Image _____

So, this practice problem wants us to match the following key terms that we see below with their appropriate image, either image a on the left or image b on the right. And so, option a here says HbS, and, of course, this is the abbreviation for sickle cell hemoglobin. And, of course, that's going to be associated with image b over here, which is showing a zoomed-in version of the bloodstream. You can see that we have this large blockage of our bloodstream here. And we know that's associated with sickle cell hemoglobin. And so we can go ahead and say that this is associated with image b. Now HbA recalls the abbreviation for adult normal hemoglobin, and so that's going to be associated with image a, which is a zoom in of the bloodstream that shows proper flow of our red blood cells. And so again, that's associated with image a. Now, malaria resistance, recall from our previous lesson videos, is associated with sickle cell. And so, because image b is associated with sickle cell, malaria resistance is going to be associated with image B. Now, heterozygous individuals for the sickle cell trait, we know, do not display the full characteristics of sickle cells. So they don't have nearly as many complications as individuals that are homozygous for sickle cell. And so they're not going to have quite as much of a blockage like we would expect to see here, and it would be more so of proper flow, like what we see here in image a. So this is a tricky one, but we're going to say that it's more so associated with image a because they don't have the complications that are associated with homozygous sickle cell individuals. Now, option e says, homozygous AA, which recall from our previous lesson video is just the homozygous for the normal allele. And so, that's going to be associated with image a as well. Now, low red blood cell count, we know is really just referring to the term anemia. And, of course, that's going to be associated with sickle cell anemia and that's going to be associated with image b over here. So we can go ahead and put b here. And then, g here says, RNA sequence is GAG, which recall from our previous lesson video is just going to be coding for glutamate or glutamic acid. So, that is going to be the negatively charged amino acid. It's going to be associated with the normal version, which is image a. And then GUG, here for H, is, of course, going to code for the amino acid valine and that's going to lead to sickle cell and image B. So, that's associated with image b. And so this here concludes our practice problem and I'll see you guys in our next video.

Researchers investigating the sickle-cell mutation want to separate the mutant hemoglobin protein (HbS) from the normal adult hemoglobin (HbA) that was extracted from a heterozygous patient's blood serum sample. In order to do this, they perform gel electrophoresis at a pH of 8.5, where most normal hemoglobin proteins are negatively charged. The protein sample is added to the negative pole and migrates towards the positive pole when current is applied. The result of the gel is shown below. Label which band represent HbS and which band represents HbA.

This practice problem says researchers investigating the sickle cell mutation want to separate the mutant hemoglobin protein HbS from the normal adult hemoglobin HbA that was extracted from a heterozygous patient's blood serum sample. In order to do this, they perform gel electrophoresis at a pH of 8.5 where most of the normal hemoglobin proteins are negatively charged. The protein sample is added to the negative pole and migrates towards the positive pole when the current is applied. The result of the gel is shown below, and the problem is asking us to label which band represents HbS and which band represents HbA. Notice down below we have our electrophoresis gel here where we have the negative end on this side and the positive end on the other. We see two bands, and we need to label them as either HbA or HbS. What we need to recall is the particular mutation that occurs in the sickle cell hemoglobin. Recall from our previous videos that sickle cell hemoglobin has a valine amino acid residue, whereas the normal hemoglobin has a glutamic acid residue at this position. The glutamate is going to have a negative charge on it, whereas the valine is going to be neutral. Because HbA has more of a negative charge associated with it, we expect it to travel further in the gel towards the positive end. Essentially, what we're saying here is that HbA, we expect to be right here at this band traveling a further distance than HbS, which we expect to travel a smaller distance here. This concludes this practice problem, and I'll see you guys in our next video.

Here’s what students ask on this topic:

What causes sickle cell anemia at the molecular level?

Sickle cell anemia is caused by a homozygous point mutation in the gene coding for the beta subunit of hemoglobin. Specifically, this mutation changes the amino acid at the 6th position from glutamate, which is negatively charged, to valine, a neutral amino acid. This single nucleotide change leads to the production of hemoglobin S (HbS) instead of the normal hemoglobin A (HbA). The hydrophobic valine residues cause the hemoglobin molecules to aggregate, forming long chains that deform red blood cells into a sickle shape. These sickled cells can obstruct blood flow and are more prone to rupture, leading to anemia and other health complications.

How does sickle cell anemia affect blood circulation?

Sickle cell anemia affects blood circulation by causing red blood cells to deform into a sickle shape. These sickled cells are less flexible and can become trapped in small blood vessels, leading to blockages or occlusions. This impaired blood flow can result in reduced oxygen delivery to tissues and organs, causing pain and potential organ damage. Additionally, sickled cells are more prone to rupture, leading to a lower red blood cell count (anemia), which further exacerbates the problem by reducing the overall oxygen-carrying capacity of the blood.

What are the health complications associated with sickle cell anemia?

Health complications of sickle cell anemia include chronic pain, increased risk of infections, and organ damage. The sickled red blood cells can block blood flow, leading to pain episodes known as sickle cell crises. These blockages can also cause damage to organs such as the spleen, liver, and kidneys. Additionally, the frequent rupture of sickled cells leads to anemia, which can cause fatigue and weakness. Patients with sickle cell anemia are also more susceptible to infections due to spleen damage, which impairs the body's ability to filter bacteria from the blood.

How does sickle cell anemia provide resistance to malaria?

Individuals who are heterozygous for the sickle cell trait (carrying one normal hemoglobin gene and one mutated gene) have some resistance to malaria. The exact mechanism is not fully understood, but it is believed that the presence of some sickled cells makes it more difficult for the malaria parasite to thrive. These individuals do not suffer from the severe health issues associated with sickle cell anemia but still gain the protective benefit against malaria. This selective advantage explains why the sickle cell trait is more prevalent in regions where malaria is common.

What is the difference between homozygous and heterozygous sickle cell conditions?

In homozygous sickle cell conditions, an individual has two copies of the mutated gene for the beta subunit of hemoglobin, leading to severe sickle cell disease. These individuals produce hemoglobin S (HbS) exclusively, resulting in the characteristic sickled red blood cells and associated health complications. In heterozygous conditions, an individual has one normal hemoglobin gene and one mutated gene. These individuals produce both normal hemoglobin A (HbA) and hemoglobin S (HbS), usually resulting in no or mild symptoms. Heterozygous individuals also have resistance to malaria, providing a selective advantage in malaria-endemic regions.