Putting sleeping sickness on the radar

It is the start of an invasion. There are no gunfire or explosions, just the mundane tickle of a fly landing on your skin. In Sub-Saharan Africa, this moment can be just as deadly as bombs and guns if that tickle is a blood-sucking tsetse fly. As the fly bites, the tiny protozoan parasites that cause sleeping sickness rush into your blood stream. What was a brief brush of legs and wings is suddenly a potential death sentence.

Your body is now a battlefield. The parasites begin to multiply and overwhelm your defences, causing waves of fever as you try to fight back. If you are lucky, you get an accurate early diagnosis and access to one of the two drugs available for the first stage of the disease. If you are unlucky, you are diagnosed late, when your brain is already crawling with the parasite and you begin to lose your mind.

The most commonly used drug of the three licensed for the second stage was discovered 90 years ago and is based on arsenic. There is a 10% chance the drug will kill you because it is so toxic; but what choice do you have? It’s a hopeless war; sleeping sickness invariably progresses to coma and death if you do not get treatment.

In Sub-Saharan Africa, the chances are you will not receive safe, effective drugs, and you will die from the disease or its treatment. The World Health Organisation estimates that there are between 50,000 and 70,000 people with sleeping sickness in Africa, and that millions more are at risk. Even if a person isn’t infected with the disease it still devastates lives, because it infects and kills livestock, too. Sleeping sickness is a disease that is crying out for more research and better drugs. However, if we are to outwit the enemy, we need to understand what makes it such a lethal foe.

The sleeping sickness parasites are superbly designed for stealth; to succeed they must evade the defences of the human immune system. The shock troops of the innate immune system rapidly and indiscriminately attack foreign cells, while the adaptive immune system learns the signature of each invading pathogen, and launches powerful, surgical strikes. But the surface of the parasite bristles with an incredibly sophisticated coat of armour that is made up of millions of protein chains anchored to the cell surface. The armour repels the barrage of the innate immune system, and by the time the adaptive immune system has locked on to its target, the parasite has shed the old armour and replaced it with new, different proteins. The surgical strikes never find their target. The parasite flies under the immune system radar, allowing it to silently multiply and invade the body.

But what if we could strip the parasite of its armour? The parasites would be visible and vulnerable to the immune system. My research focuses on the anchor that holds the armour’s protein bristles in place on the surface of the parasite. If the parasite cannot make the anchor, then it cannot make its coat of armour. The parasite has a production line for assembling the anchor; it is built up, piece by piece, by a series of molecular machines known as enzymes. I design and synthesize molecules that mimic the anchor at a particular stage of its production. The mimics fit into the enzyme, but instead of allowing it to add the next piece of the anchor they jam the machine and stop it working. Once the anchor production pathway is shut down, the parasite loses its armour.

Making these anchor-mimic molecules is slow and laborious because we do not know the structure of the enzyme we are trying to inhibit. It is like trying to guess the structure of a lock by making many different keys and seeing how they fit. But every molecule I make brings me closer to stripping the stealth armour from the sleeping sickness parasite, and finally letting the good guys win.

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