- Did you ever see that movie "Powers of Ten?"

A couple of picnics in the park, the camera zooms away to show us the whole galaxy, then zooms all the way back in to show us the atoms in the hands of one of them.

Well, following that same principle, let's take a look at the bark of the Cinchona tree used to fight malaria Zoom way in, and we see, by total coincidence, the molecule quinine binds to an enzyme that is essential to the malaria parasite survival.

Zoom all the way out, and you can see, how it may have caused World War I.

(rhythmic marching band music) (device dings loudly) (lid pops softly) Late last year, the World Health Organization authorized the first malaria vaccine.

Of course, we've all been very preoccupied with another disease plaguing the world.

But this vaccine is a big deal.

Even amid the COVID crisis, 2020 saw nearly a quarter of a billion malaria cases and 627,000 deaths.

Getting a completely accurate estimate of the historical death toll of malaria is impossible.

The best I can give you is a pretty broad range.

But scientists estimate between 16 and 50% of all people ever born have died of malaria.

And because of that, malaria has a substantial impact on our genes.

One in 14 humans carries a mutation that evolved to defend us from this plague.

West Africa was so lethal to Europeans, it was called the White man's grave.

The Sierra Leone command lost as many as 483 per 1000 people.

And what's known as Ghana, lost as many as 668 per 1000 people.

Malaria is a nasty business.

It's caused by five species of parasite that infect both humans and mosquitoes.

Plus, it's sneaky.

A person bitten by an infected mosquito will not display symptoms immediately.

No, the newly released parasites squiggle their way over to the liver.

Cloak themselves in liver cells, evading the immune system and only then do they start dividing.

Once the parasites proliferate, they invade the bloodstream and digest hemoglobin, further enabling their reproduction.

And it's in this hemoglobin gobbling stage that a person starts to experience flu-like symptoms like shaking, chills, headaches muscle aches, nausea, and more.

If another mosquito bites the infected person in this phase, the mosquito gets infected and the cycle continues.

Most adults survive malaria, but many babies and small children can progress to severe malaria, which is often fatal.

So when missionaries returned from Peru with a bark called Jesuits' powder that seemingly prevented malaria and reduced the severity of the disease once contracted, the trajectory of colonization took a little nudge.

It comes from the bark of the Cinchona tree.

The most commonly used ingredient in that powder became known as quinine.

To make the bitter quinine a little more tolerable, people started adding carbonated water and a healthy dose of sugar and started calling it tonic water.

There really isn't enough quinine for it to be therapeutic, unless one drinks, gallons, and gallons of it.

But once quinine made its way to Europe, it became a powerful tool to expedite colonization.

In 1870, roughly 10% of Africa was colonized, mostly on the coasts.

By 1914, it was 90%.

This rapid partitioning and colonization of the continent is known as the Scramble for Africa.

While malaria wasn't the only disease contributing to the White man's great reputation, the introduction of quinine in the mid 19th century, caused death rates among colonizers to plummet and supercharged Europeans' conquest.

And of course, the major European powers of the time, including the newly formed German empire didn't wanna just fight each other while subjugating an entire continent.

So they drew lines through the Berlin Conference and other agreements, and of course, without consulting any African representatives, those major powers of Europe just partitioned Africa for themselves.

But there were ongoing disagreements like the Moroccan Crisis where Kaiser Wilhelm II pushed for Moroccan independence from France.

The struggle for military and economic control over the Northern African nation ratcheted up tensions through Europe, forcing other nations to take sides and form secret alliances while everyone was looking for opportunities to strengthen their own position and weaken that of their European neighbors.

Not everyone in Europe was happy with the way that Africa was being divided up, not to mention how the actual people of Africa felt about it.

There was a growing sense of grievance and distrust among these colonial powers.

The colonization of Africa was a pressure cooker for the European rivalries.

Fueling the fire under that pressure cooker was quinine.

It was a miracle drug and medically liberating for millions of people and it was used so oppressively.

So how does quinine come to the rescue?

Well, at the time they had no idea.

They just knew that it works.

But now, with all the modern scientific tools at our disposal, we're still not 100% sure to be honest.

But a recent study using a method from the anti-cancer drug research, may have finally offered us the answer.

Here is what we know about quinine for sure.

It's an alkaloid, meaning that it naturally occurs in plants and contains nitrogen.

Cinchona bark has a total of four alkaloids that will work to kill malaria parasites, quinine, cinchonine, cinchonidine and quinidine.

But quinine was specifically chosen out of the four because it became clean white powder when isolated.

As far as what it does in the body, we know it only helps during certain stages of the infection.

It won't, for example, prevent the malaria parasite from entering the body and working its way to the liver.

But with daily quinine use, it can actually prevent the parasite from moving beyond this stage and invading the bloodstream, which is when the malaria symptoms start.

If an infected person stops taking the prophylactic quinine, they can abruptly enter the symptomatic phase.

It needs to be taken every day to be effective.

(door creaks softly) These days, we have synthetic anti-malarial drugs and we have a pretty good idea of how they work.

I have these leftover from my last trip to South America.

(pills rattle softly) However, over the past century, new strains of drug resistant malaria parasites have evolved to evade the synthetics.

But OG quinine is still effective.

It is obviously doing something right.

So if we want to develop new drugs to fight malaria, it would be really helpful if we could figure out what exactly Quine is doing that is so effective.

And that's why this is so exciting.

Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay.

Let's break that down into regular English.

These researchers use a technique called cellular thermal shift assay, coupled with mass spectrometry.

Good old MS-CETSA, everyone's favorite.

CETSA was invented to help develop anti-cancer drugs.

The basic idea is that when you heat a cell up.

some of the proteins denature and unfold, and when they do that, they precipitate and fall out of a solution.

Different proteins unfold at different temperatures, which means that by heating up a cell to a specific level, you can control which proteins are left in solution.

But, and this is the important bit, when a drug binds to a protein, it significantly changes that proteins thermal stability.

So when using samples heated up to a range of different temperatures and comparing samples with and without quinine, researchers were able to figure out which protein within the malaria parasite's cell was binding with quinine.

And what is the exciting conclusion?

Can I get a drum roll for this?

The target protein of quinine appears to be plasmodium falciparum purine nucleoside phosphorylase.

I'm not going to say that again.

If you want the full name, you're gonna have to rewind.

PfPNP for short.

PfPNP is an enzyme, as you may have already gathered from the fact that it ends in ase.

The phosphorylase.

And no, I'm not gonna say the full name again.

But it's an important enzyme for the malaria parasites.

Now, these parasites are known as purine auxotrophs.

Purines in the context, refers to the two DNA bases, adenine and guanine.

And auxotroph means that the malaria parasites can't make their own and need to get it from their host.

So in other words, in order for these parasites to replicate inside their host, they need to steal the host's adenine and guanine and recycle it into their own DNA.

The enzyme that they use to do this is the PfPNP.

What appears to happen is that the quinine nestles into the PfPNP, like a wrench in some gears, preventing the plasmodium cell from grabbing those precious purines.

Now, we don't know this for sure yet.

This is just one study.

And while they've shown that the quinine binds to the PfPNP, we don't have confirmation that it is in fact quinine's mechanism of action yet.

But we have a promising lead.

And after hundreds of years of quinine use and in the face of a disease which may have killed as many as half of all humans who have ever lived, a promising lead is pretty exciting.

So the quinine binds to the PfPNP and that might be how it protects people from becoming symptomatic with malaria.

(bell dings softly) That protection allowed more European colonizers to reach deeper into the continent and may have been a major contributing factor to enabling the Scramble for Africa.

Now, the Scramble for Africa contributed to the tensions between European colonial powers.

And those tensions and the forces of colonialism and imperialism in general, ultimately boiled over into World War I.

So did quinine cause World War I?

No, of course not.

Quinine didn't shoot Archduke Franz Ferdinand.

I mean, the title is a bit hyperbolic but you knew that, right, but it's a really interesting thing to think about.

And at least I think so.

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