'Glow in the dark' quinine could help kill malaria parasite

05 September 2014 | Story by Newsroom
A mosquito waits, poised, on a blade of greenery.
A mosquito waits, poised, on a blade of greenery.

For centuries it was the treatment of choice against malaria '“ until new drugs with fewer side effects came along.

Today, quinine is not only useful as an ingredient in the tonic water accompanying your gin; it could also be the key to uncovering the malaria parasite's most toxic secret.

It's difficult to overstate the economic burden caused by malaria. With one person '“ typically, a child under the age of five in sub-Saharan Africa '“ dying from the disease every 30 seconds, and with climate change threatening to expand the 'malaria belt' (the global tropical region in which malaria is found), the race is on to meet the United Nations' Millennium Development Goal of reducing the incidence of malaria by next year.

'Know thy enemy', the military strategists suggest, and scientists have recently taken this advice to heart. Many scientists have declared that it is time to go '˜back to basics' on research into the world's most crippling infectious diseases, after the unsuccessful run of a candidate vaccine for HIV known as the STEP trial, which appeared to increase the susceptibility of patients to the virus.

In the case of the rapidly evolving malaria parasite, there is an urgent need to better understand its biology. The parasite spends half of its lifecycle in the mosquito and the other half in the human host. If you are unlucky enough to be bitten by an infected mosquito, the parasite first makes its way to your liver and then invades your red blood cells. There it begins to consume haemoglobin (the oxygen-carrying protein in your blood cells) to survive and grow.

It is at this point that the parasite spills its toxic secret. To know the secret, you need to know that haemoglobin is made up of four special molecules called 'haem', each of which is tightly bound to an amino-acid chain called 'globin' (hence the name 'haemoglobin'). During digestion of the haemoglobin inside the parasite, the haem molecule is released from its globin chain. This liberated or 'free' haem is poisonous to the parasite and causes it all kinds of cellular damage. But the malaria parasite has evolved an ingenious detoxification system to rid itself of this free haem: it stores haem in crystal form in its digestive compartment, like a harmless stone.

Imagine if it were possible to turn this detoxification process against the parasite? Interrupting the crystallisation pathway would lead to a lethal accumulation of haem that would overwhelm and poison it, but not us.

The gold standard in drug discovery is to target a metabolic pathway that is unique to the pathogen. In this case, interrupting the crystallisation of haem would be fatal for the parasite, but not the host '” the parasite's Achilles' heel.

To design a detoxification-disrupting drug, we need to know exactly where the haem is located in the parasite. So how do we go about '˜seeing' a specific molecule among so many others?

Even though we have developed many sophisticated imaging techniques, haem continues to elude us. We can't 'see' it using conventional scientific instruments '“ even though we know that it is lurking in the parasite. It is essentially invisible to our eyes. So we need to employ another agent '“ a molecular spy '“ to see it for us. For this, we need to call on quinine.

It is said that quinine has benefited more people over the centuries than any other drug in the fight against infectious diseases. It originated in South America, where it occurs naturally in the bark of the cinchona tree. According to an ancient Peruvian legend, a man with a high fever was lost in the jungle. Thirsty, he drank from a pool of stagnant water and found that it tasted bitter. He realised that the water had been contaminated by the surrounding cinchona trees, and thought that he had been poisoned. Surprisingly, his fever soon abated and he was able to share this accidental discovery of quinine with his fellow villagers.

Quinine eventually found its way to Europe and was the antimalarial drug of choice for centuries, until newer, more effective molecules with improved tolerance were developed.

Even if it is no longer the first choice in treating malaria, quinine is uniquely positioned as our molecule of choice to seek out haem in the parasite. First, it has a high affinity for haem, meaning that it binds strongly and specifically to the haem molecule. Second, quinine is highly fluorescent. This means that under a microscope, quinine lights up like a veld fire in the night.

Fluorescence has revolutionised the study of biological cells. By exploiting these special molecules that literally 'glow in the dark', we can see things in cells that we would never otherwise have been able to see. Today, biologists have a host of fluorescent dyes and proteins at their disposal to illuminate particular areas or molecules within a cell.

That is why, in my research project, we are using quinine, with its natural affinity for haem and its innate fluorescence, as a key molecule for understanding the malaria parasite's metabolism. If quinine can help us to track down the haem in the parasite, we can use this crucial information to inform the design of new antimalarial agents. And then we might be able to help to turn the tide on this scourge.

So next time you sit back to enjoy a gin and tonic, pause for a moment to appreciate the quinine in your tonic water. It has already saved millions of lives, and might still save more. Except this time, it will help us to see the invisible.

John Woodland is a PhD candidate at the University of Cape Town.

This article first appeared in the Mail & Guardian as a part of their Science Voices supplement.

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