And now for the exciting conclusion to these two posts.  

Disclaimer: I’m not a doctor – just a bioengineer who happens to find pathophysiology fascinating.  If you find an error, please let me know!  Also, NONE of my drawings are to scale.

In this post, we looked at how one tiny change in a person’s DNA caused her to suffer from sickle cell anemia.  We learned that, untreated, about 50% of children with sickle cell anemia die before their fifth birthday.  If you understand natural selection, you’ll recognize this as a puzzle: if sickle cell anemia is so deadly, why are there so many people still affected by it?  Let me explain the puzzle a little further.

For almost all traits, a person has two copies of instructions: one from her father and one from her mother.  Sickle cell disease is autosomal recessive – which just means that both parents must pass on the sickle cell trait for the child to be sick.  People who only received the trait from one parent aren’t sick, but can pass the disease on to their children.

In most cases where an autosomal recessive trait is deadly early in childhood, the disease dies out.  A child affected by the disease won’t live to have children of his own, and thus won’t pass down the bad information.  With no one to pass it on, the disease stops.

But, sickle cell disease hasn’t followed that pattern.  In some parts of Africa, 40% of the people carry the trait.  Whoa!  There must be a piece of the puzzle we’re missing.

In the 1950s, Dr. A.C. Allison saw maps like the ones below and wondered if there could be a connection.  One map shows places where sickle cell anemia is common, and the other shows places where malaria was common.

 See how similar they are?  It turns out that having one copy of the sickle cell gene gives people some protection from malaria. People who had one copy of the sickle cell gene didn’t die of sickle cell and they didn’t die of malaria, so they survived to have children.  Even though this pattern meant many kids inherited two copies of the sickle cell gene and died of sickle cell disease, enough people with one copy survived to keep the gene alive.  Because humans have been fighting malaria for, well, all of human history, we’ve had time to develop a natural way to win the fight by changing our DNA.

“Well, why?  Why does having one copy of sickle cell protect you from malaria?” you might ask.  It’s a question many scientists are asking as they search for a cure for malaria, and they haven’t quite settled on an answer.  Let’s look at a few leading contenders.

But first, some notation.  People with one copy of the sickle cell gene are said to have sickle cell trait (not disease) or are heterozygotes for sickle cell.  The prefix hetero- means different: heterozygotes have two different sets of instructions: a normal hemoglobin (HbA) and a sickled hemoglobin (HbS).  I’ll call them heterozygotes for the rest of this post.

Heterozygotes make some normal hemoglobin (HbA) and some sickled hemoglobin (HbS).  In most circumstances, there’s enough normal hemoglobin to keep the person from being sick – the normal hemoglobin molecules prevent the sickle hemoglobin molecules from sticking together.

Also, to clarify: heterozygotes still get malaria – they just tend to survive the encounter more often than anyone else.  As Dr. Luzzatto put it, “[For heterozygotes,] the phrase ‘malaria-resistant’ ought to be regarded as shorthand for ‘relatively protected from dying of malaria.’”

Today we’ll be talking about Jane – Jill’s sister.  Jane is a heterozygote for sickle cell.

Here are some leading theories on why Jane and other heterozygotes tend to survive malaria.

1. Malaria parasites have a harder time entering the red blood cells of heterozygotes.

Though this idea is popular among lay scientists, there’s actually very little evidence for it.  Malaria parasites appear often inside heterozygote red blood cells when you look at them under a microscope.

1. Sickled cells kill malaria parasites.

This theory says that when infected red blood cells sickle (change shape), the malaria parasites essentially get squished and die.

“But wait,” you say, “I thought only people with two copies of the sickle cell gene had sickled cells?  Isn’t that why they’re the only ones to get sick?”

Good catch!  It turns out that people with sickle cell disease (two copies of the gene, also known as homozygotes) sickle when oxygen is “normally” low, like in muscles and veins.  If the amount of oxygen gets really low, heterozygotes can sickle, too.

Malaria makes the amount of oxygen get really low.  The parasite, in its normal “breathing” inside the red blood cell, releases carbon dioxide – a lot of it.  The hemoglobin molecules think, “Oh no!  Jane really needs oxygen right now!  Release, release!”

As you’ll remember from the last post, releasing all that oxygen frees up binding sites on the sickle hemoglobin.  In this super-low oxygen state, many more of the sickle hemoglobin molecules become “sticky” than normal.  When that happens, they pull together (leaving the normal hemoglobin out) and form the long strands that cause the cell to sickle. Thankfully, that tends to kill the parasite.  Whew.

2. The body attacks the abnormal, sickled cells, and gets the malaria parasite for free.

Last time, we talked about how the spleen tends to gobble up and destroy any cells that are sickled.  When the malaria parasite causes the heterozygote’s cells to sickle, it also alerts the body to get rid of the cell.  In getting rid of the sickled cell, the spleen kills the malaria parasite, too.  Excellent.

3. Infected red blood cells don’t stick to the blood vessel walls very well.

When malaria infects a normal person, it tries to avoid destruction in the spleen by attaching to blood vessel walls (read more here).  If enough parasites do this in an important place, the patient gets very sick.  When it happens in the brain, we call it “cerebral malaria,” and most people with this condition die.

In heterozygotes (and homozygotes), the red blood cell “ropes” that the parasite uses to latch on to the vessel wall are broken up by the long chains of sickle hemoglobin.  Thus, fewer cells get stuck in the brain or lungs, and the patient can survive.

Scientists are really interested in understanding this method better.  While many heterozygotes still get sick from malaria, very few of them die – mostly because they don’t get cerebral malaria.

4. Heterozygotes survive until they develop immunity to malaria.

Most people who die of malaria are young children.  Their bodies have outgrown the protection their mother gave them when she nursed them, but they haven’t grown up enough yet to learn how to fight malaria on their own.  We think that Jane’s advantages (listed above) give her just enough of a leg up that she’ll survive until her immune system can fight off the parasite.

 

For humans living in areas where malaria is common, it’s an evolutionary choice between two evils:

If you get 2 copies of the sickle cell gene, you tend to die young from complications of sickle cell.

If you get 0 copies of the sickle cell gene, you tend to die young from malaria.

If you’re just lucky enough to get 1 sickle cell gene, you’ll probably survive to have children, but you might pass down a deadly disease.

Until humans can find a way to finally stop our ancient enemy of malaria, we’ll continue to pass down the sickle cell gene – a sharp weapon that can protect or kill.

 

Sources and Further Reading

There are, naturally, even more theories about how sickle cell protects against malaria that I didn’t go into here.  You can read about them (as well as my wonderful references) at the links below:

• The original paper linking sickle cell and malaria: Allison, A.C. Protection Afforded by Sickle-Cell Trait Against Subtertian Malarial Infection. British Medical Journal. 1954; 290-294. 
• A wonderful source for many of the mechanisms I discussed that also includes some ideas about why homozygotes for sickle cell are not protected from malaria: Luzzatto, Lucio. Sickle Cell Anaemia and Malaria. Mediterranean Journal of Hematology and Infectious Diseases. 2012; 4(1) e2012065, DOI 10.4084/MJHID.2012.065.
• Mechanism of sickling of cells killing the parasite: Friedman, Milton. Erythrocytic mechanism of sickle cell resistance to malaria. PNAS. 1978; 75(4) 1994-1997.
• Mechanism of decreased RBC stickiness: Cyrklaff, Marek et al. Hemoglobins S and C Interfere with Actin Remodeling in Plasmodium falciparum-Infected Erythrocytes.  Science. 2011; 334(6060) 1283-1286.
• Prevalence of sickle cell: World Health Organization. Sickle-cell anaemia. 2006.
• Details and mystery: What is Cerebral Malaria?
• New mechanism – enzyme induced by sickle hemoglobin protects against cerebral malaria: Mystery Solved: How Sickle Hemoglobin Protects Against Malaria. Science Daily. April 29, 2011.