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Captain Kirk vs. malaria
The world’s deadliest shapeshifter
The malaria parasite is good at fooling your immune system. Now scientists are fighting back.
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It’s Mosquito Week again on the Gates Notes. In this post I write about how the malaria parasite changes shape to foil your immune system. I’ve also written about ingenious new genetic techniques for fighting mosquitoes and maps that could help us defeat malaria.

I remember an old episode of the original Star Trek where the bad guy is a shapeshifter who turns himself into a second Captain Kirk. There’s a great scene at the end where Spock has to figure out which one is the impostor.

Shapeshifters are not just the stuff of science fiction, though. We have them right here on earth. Some are innocuous, like a caterpillar turning into a butterfly. But there’s another shapeshifter that’s responsible for more than 400,000 deaths every year. I’m talking about the group of microscopic parasites that cause malaria.

Malaria is one of the most fascinating and frustrating diseases our foundation works on, and its ability to change shape is one of the main reasons why. These parasites have figured out ingenious ways to fool your immune system. They have also (mostly) evaded our best efforts to make a malaria vaccine.

To understand how, it helps to know a bit about how your immune system works.

“I’ve never seen the funny shape on the outside of this thing. I’m going to attack it.”

Your system is very good at detecting unusual objects in your body. It looks at the proteins on the surface of an invader and says, “I’ve never seen the funny shape on the outside of this thing. I’m going to attack it.” After the invader is defeated, your body remembers what it looked like and will go after it if it ever shows up again. Vaccines work by taking advantage of this process. When you get a measles shot, it contains a little bit of the virus; it won’t make you sick, but your body learns how to defend itself against future infections.

Unfortunately, malaria is a lot more complex than viruses or bacteria. For one thing, it is caused by parasites. Parasites don’t look as weird to your body as viruses or bacteria do. In fact, they more closely resemble your own cells, so your immune system has a harder time fighting them off.

Another problem is that the malaria parasite goes through three different stages in your body. It looks radically different in each stage, and as the infection goes on, you have all three going on at once.

Stage 1 begins when an infected mosquito bites you and injects a little saliva under your skin. This dose of saliva might contain only 100 parasites (called sporozoites in this stage). They are small and don’t cause any inflammation in your body, so your immune system doesn’t bother to look for them. You’re not feeling any symptoms yet.

Within an hour or two, the sporozoites make their way to your liver for stage 2. Coming out of your liver, they take a new form (called merozoites) and start invading your red blood cells. This invasion causes the symptoms—fever, chills, and so on—that make malaria such a miserable and deadly disease.

Now your body knows it’s sick and your immune system kicks in. But this is where the parasite’s shapeshifting comes into play.

Remember how the measles vaccine helps your immune system learn to identify the virus by looking for certain proteins on its surface? That works because those proteins look the same on each clone of the measles virus in your body. With malaria, each one can present up to 60 different proteins—and thanks to a mechanism that tells the parasite to alter its surface periodically, they shuffle these proteins around in different combinations every few days.

“It’s as if there’s a door on the surface of the parasite, but it keeps changing the locks.”

As a result, by the time your immune system has figured out how to attack one shape, the parasite has transformed, and your body’s defenses are useless. Your immune system adjusts, but not before the parasite has shifted again. It’s as if there’s a door on the surface of the parasite, but it keeps changing the locks so your body never has the right key.

Finally, in stage 3, a few of the merozoites develop into male and female cells. These hang out in your bloodstream, waiting for the next mosquito to come bite you. Once they’re in the mosquito’s stomach, they form new sporozoites, which make their way to the bug’s saliva glands and get injected into the next human, where the cycle starts all over again.

So that is the life cycle of malaria. What does all this mean for the effort to control and eventually eradicate this disease?

You might think we could create a vaccine that simply recognizes all the different shapes of the parasite. Unfortunately, that’s not practical. The only vaccine we have ever done that with is for a type of pneumonia. It is very expensive to manufacture and covers only a dozen shapes or so, versus the 60 shapes in one malaria infection and the many hundreds across all malaria parasites worldwide.

The malaria community (including our foundation) has been working for years on a vaccine to protect you in stage 1, before the infection takes hold. This vaccine, called RTS,S, teaches your immune system to hunt for a bit of protein that is always on the surface of the parasite. Unfortunately, the protection provided by RTS,S is not strong enough for long enough to help us make real headway toward eradication. And there are other forms of protection (such as bednets and insecticides) that are more cost-effective for saving lives.

People often ask me if it’s frustrating to fund work that takes so long to come to fruition. My answer is: not at all. Of course, I’m disappointed that we don’t have a long-lasting vaccine yet. But this is hard work. Parasites are such complex organisms that there are no effective vaccines for any of the human diseases that they cause. Besides, the research on RTS,S has given scientists a lot of insight into how malaria works and new clues about how to stop it. In fact, much of what we know about how your body responds (or fails to respond) to this type of parasite came from research on RTS,S.

The malaria community is now building on this knowledge. For example, scientists are working on new approaches that we hope will trigger the immune system to create long-lived, antibody-generating cells. Another promising idea is to create synthetic antibodies rather than trying to get your immune system to make natural ones. These monoclonal antibodies have revolutionized the treatment of cancer and inflammatory disease, and they could do the same for infectious diseases like malaria.

Knowing how complex malaria is helps me appreciate how much progress the world has made in fighting it. Deaths from malaria have dropped 42 percent since 2000, thanks to investments in bednets that prevent it and medicines that cure it. When I see how far we have come and how much we have learned, I am as optimistic as ever that we can beat this clever shapeshifter.

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