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 here1.  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.

Sources and Further Reading

    • Plush toys to help you remember to always wear bug spray. Or a mosquito to take out your revenge on. (Affiliate links – thanks for supporting us!)
  1. 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. []