Tag Archives: Malaria

Malaria, Where is Thy Sting?

“This day relenting God hath placed within my hand, a wondrous thing; and God be praised.  At His command,

Seeking His secret deeds with tears and toiling breath, I find thy cunning seeds, O million-murdering Death.

I know this little thing a myriad men will save. O Death, where is thy sting? Thy victory, O Grave?”

– Ronald Ross, 1897 – after discovering that malaria lives in a mosquito’s stomach

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Sickle Cell and Malaria: A Double-Edged Sword

The fourth post bringing the exciting world of pathophysiology to light, tying together these two posts.  

I’m about ready to launch this series as its own blog!  … once I find a name for it.  If you have any ideas, please let me know in the comments!

And now, for our exciting conclusion…

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 this case, Mom and Dad are both carriers of a genetic disease.  Statistically, 1/4 of their children will be completely healthy, 1/2 of their children will be healthy carriers of the disease, and 1/4 of their children will be sick.

In this case, Mom and Dad are both carriers of a genetic disease. Statistically, 1/4 of their children will be completely healthy, 1/2 of their children will be healthy carriers of the disease, and 1/4 of their children will be sick.

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.

Distribution of sickle cell trait.

Historical distribution of malaria.

 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.

Inheritance of the sickle cell trait when malaria is around.  Of the parents' four children - statistically speaking - one will have no sickle cell and will die young of malaria, and one will have sickle cell anemia and die young.  The two children who survive to adulthood will be carriers of the sickle cell trait.  They will marry other carriers - since these carriers are likely to have survived, too - and the cycle continues.

Inheritance of the sickle cell trait when malaria is around. Of the top parents’ four children – statistically speaking – one will have no sickle cell and will die young of malaria, and one will have sickle cell anemia and die young. The two children who survive to adulthood will be carriers of the sickle cell trait. They will marry other carriers – since these carriers are likely to have survived, too – and the cycle continues.

“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.

There's enough normal hemoglobin in a red blood cell to keep the sickle hemoglobin from sticking together.

There’s enough normal hemoglobin in a red blood cell of a heterozygote to keep the sickle hemoglobin 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.

Malaria entering a red blood cell.

Malaria entering a red blood cell.

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!”

Sickle and normal hemoglobin molecules release all their oxygen when a malaria parasite breathes out carbon dioxide.

Sickle and normal hemoglobin molecules release all their oxygen when a malaria parasite breathes out carbon dioxide.

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.

Strands of sickle hemoglobin strangle the malaria parasite.  Normal hemoglobin enjoys watching its friends finally do something useful!

Strands of sickle hemoglobin strangle the malaria parasite. Normal hemoglobin enjoys watching its friends finally do something useful!

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.

The spleen sorts through red blood cells and gets rid of the bad ones.

The spleen sorts through red blood cells and gets rid of the bad ones.

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.

The body's immune system fights off malaria.

The body’s immune system fights off malaria.

 

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.

 

 

References & 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:

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Malaria – An Ancient Struggle

The third post bringing the exciting world of pathophysiology to light.  (We might be approaching a series here!) Before we discuss why sickle cell anemia has persisted for so long, let’s take a detour to learn about once of the most ancient human diseases: malaria.  

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.

Malaria: scourge of the human race since time immemorial.  The disease is mentioned by the ancient Chinese, Egyptians, Greeks, and Sumerians as far back as 2700 BC.  Some Biblical scholars even believe that Peter’s mother-in-law was suffering from malaria before Jesus healed her.

Unlike the ancient scholars who attributed malaria to the “bad air” (mala aria) of the swamps, we now know that malaria is spread by mosquitoes (who, as it so happens, absolutely love swamps.  You were close, ancient scholars).  But what happens after that terrible bite?  How does malaria make you sick?

I’m glad you asked.

Jill’s not.  She’s about to fight for her life.

Malaria - Grumpy Jill

When the evil mosquito bites Jill, it injects a small amount of mosquito spit to keep Jill’s blood from clotting so that the mosquito can gorge itself.  Unfortunately, this particular mosquito has been carrying around malaria parasites in its mouth, and Jill gets a shot of those, too.

Mosquito spit *and* malaria.  Lovely.

Mosquito spit and malaria. Lovely.

The worm-like mosquito parasites (called sporozoites at this point – “seed animals”) head for Jill’s liver.  Once there, they wiggle into Jill’s liver cells and hunker down.  Their goal is to make as many copies of themselves as they can before Jill’s immune system tracks them down.

Malaria hiding from the immune system in liver cells.

Malaria hiding from the immune system in liver cells.

They’ll usually work here for about 6 days; meanwhile, Jill has no idea she’s sick.

At the end of 6 days, the parasites are ready.  Each one has produced ten thousand copies of the next stage of the parasite: merozoites (“next part of an animal”).  These parasites burst out of Jill’s liver cells, but as they do so, they take some of the cell’s outer lining with them.  The parasites are literally like wolves in sheep’s clothing: by wrapping themselves in Jill’s cell, they can fool her immune system.

Malaria escapes like a wolf in sheep's clothing.

Malaria escapes like a wolf in sheep’s clothing.

These cloaked parasites move into Jill’s blood and rapidly enter her red blood cells.  Here, they feed and multiply again.  Malaria parasites eat Jill’s hemoglobin – tearing it apart to make their own proteins.  The part of hemoglobin that contains the iron (called the heme group), however, is poisonous to them, so the parasites crystallize it in a safer form called hemozoin.  (These crystals have neat optical properties – they glow in certain forms of microscopy.  Scientists are trying to use those properties to diagnose malaria more easily.)

Then, after one, two, or three days (depending on the species of malaria Jill caught), all of the parasites inside her red blood cells break out at the same time.

Malaria parasites burst two red blood cells.

Malaria parasites burst two red blood cells.

Each of the new parasites then goes to infect another red blood cell, where it multiplies for a number of days and then breaks open again.  This timeline is very consistent and causes the characteristic fever of malaria that comes and goes.

Why does the breaking of red blood cells cause fever?  Scientists aren’t really sure yet.  One theory I found thinks that the secret lies in the hemozoin that’s also released when the cells break.  The parasites accidentally trap some of their own DNA in crystals of hemozoin, and Jill’s body may be able to recognize the DNA.  When an immune cell sees the foreign DNA, it releases a ton of molecules that say, “INTRUDER ALERT!”  Her body then tries to kill the intruder by turning up the heat – fever.

Jill’s body fights back in other ways, too.  The parasite makes its host red blood cell very stiff, and the spleen (as we saw last time) is great at filtering out old, stiff red blood cells.  It pulls the infected cells out of circulation and kills the intruder. Way to go, spleen!

Unfortunately, malaria has learned to fight back against us.  Once malaria gets into the red blood cell, it puts stuff on the outer lining of the cell that makes it stickier.  That way, the cell will get stuck in the small blood vessels of Jill’s brain, lungs, kidneys, or many other important organs instead of going to the spleen to be destroyed.  If there are enough malaria parasites in Jill’s blood, these sticky cells can block blood flow to her brain or lungs.  And, as you might have guessed, having no blood get to your brain kills you.

But, not every infected red blood cell follows this path.  Some parasites are trying to make a brighter future for their children… Instead of making more merozoites, some make gametocytes – essentially malaria egg and sperm cells.  These parasites make the red blood cells less sticky: they want to be able to flow right into the mouth of the next mosquito to bite Jill, where they’ll start the whole process over again.

Some infected cells stick to the blood vessel walls, but the cells containing malaria "eggs" float free.

Some infected cells stick to the blood vessel walls, but the cells containing malaria “eggs” float free.

Unfortunately, the malaria’s not through with Jill yet.  While some parasites are multiplying in her blood and some are getting set to infect Jack, others are going to sleep.  Just like a terrorist sleeper cell, hypnozoites (“sleeping animals”) sit quietly in Jill’s liver cells, waiting for the right moment.  Unless Jill is treated properly, these cells can re-infect her months to years after that initial mosquito bite!

Sleeper cell.

Sleeper cell.

How should Jill be treated?  First, a doctor has to recognize her generic symptoms (fever) as possible malaria.  Diagnostic tests for malaria are pretty bad – the most common one has a doctor look at her blood under a microscope, hoping to see the tell-tale parasite setting up shop in a blood cell.

Let’s assume, for once, that things go Jill’s way and she gets properly diagnosed.  What can they do for her?

If Jill lived in Europe in 500 AD, doctors would have tried to make her bleed to get rid of the poisons, following the advice of the Greek doctor Galen.  However, having the malaria parasite eat her hemoglobin and then having the doctors take the rest of it would have left Jill with very little blood to carry oxygen around, and she would have died.  Sorry, Jill.

If Jill lived in Peru in the 1600s, a Jesuit priest would have given her a bitter tea made from the bark of the cinchona tree, newly discovered.  She probably would have lived.

Jill's treatment, from left to right: 500s Europe, 1600s Peru, 1700s Europe, 1800s India, modern day.

Jill’s treatment, from left to right: 500s Europe, 1600s Peru, 1700s Europe, 1800s India, modern day.

If Jill lived in Europe in the 1700s – after the discovery of the healing properties of cinchona – she probably would have died.  European physicians tried to use the bark on every fever, and found that it didn’t cure many patients (because it was only effective against malaria).  They thus concluded it didn’t work at all and stopped prescribing it.  Prescribing a hot tea to a patient suffering from fever didn’t make much sense to them, and many Protestant countries were wary of taking a drug produced and distributed exclusively by Catholic countries.  Poor Jill.

If Jill had lived in British India in the 1800s, she probably would have been given a “gin and tonic” – quinine (made from the cinchona bark) mixed with gin to mask the bitter taste.  She would have lived.

In the modern era, Jill has several options.  Most malaria can still be treated by quinine – it prevents the parasites from converting the toxic heme to hemozoin, so they essentially die in their own waste.  The synthetic version, chloroquinine, has fewer side effects, but some types of malaria are resistant to its effects.  Several other drugs have been created for these resistant parasites, but we won’t discuss them here*.  Treatment with a second drug – primaquine – kills the sleeper cells hiding in Jill’s liver so that she won’t get sick again.

What an epic struggle!  Humanity’s long battle with this tiny parasite has even changed our DNA – a mechanism we’ll look at in the next post.

Are you enjoying this series?  Have any diseases you’d like me to examine?  Or have you come up with an awesome title for this series? Let me know!

* The history of malaria treatments and the effect of major wars on these drugs is a fascinating one – I encourage you to check it out.

Sources/Further Reading

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