10,000-year-old disease that haunted Greeks and Chinese, weakened Civil War soldiers and caused 5% of 20th century deaths may finally have a weakness; Indian researchers find breakthrough

Scientists from India and Britain say they have identified a protein that controls how the malaria parasite divides and multiplies, a discovery that could lead to an entirely new class of drugs against one of history's most persistent killers.

The research, led by teams at the Biotechnology Research and Innovation Council-National Institute of Immunology in Delhi and the University of Nottingham, centres on an enzyme called Aurora-related Kinase 1, or Ark1, which appears to act as a master switch in the malaria parasite's cell division process. The findings come at a moment when the world's existing arsenal of anti-malarial drugs is under growing threat from resistance.

A disease that has followed humanity for 10,000 years


To understand why this matters, it helps to understand what malaria has done to the human species.

The parasite Plasmodium has been infecting humans since the Neolithic age. Ancient Mesopotamian clay tablets describe deadly periodic fevers. Indian texts from the Vedic period, dating to around 1500 BC, called it the "king of diseases." Malaria antigen has been detected in Egyptian remains from as far back as 3200 BC. Greek physicians including Hippocrates documented it. Roman historians linked it to the fall of Rome itself.

In the 20th century alone, malaria is estimated to have caused between 150 million and 300 million deaths, accounting for as much as 5 per cent of all human mortality. Today, the disease still kills hundreds of thousands of people every year, with sub-Saharan Africa bearing the heaviest burden. Around 40 per cent of the world's population continues to live in areas where malaria is actively transmitted.

What makes Plasmodium so difficult to defeat is its adaptability. It thrives in two completely different biological environments, the mosquito and the human body, and behaves differently in each. In mosquitoes it leeches nutrients. In humans it can evade immune defences and replicate at speed.

The drugs are running out of time

For most of modern history, the fight against malaria has been a race between drug discovery and parasite resistance, and the parasite has rarely fallen behind.

Chloroquine, once the backbone of global malaria control, began showing resistance in the late 1950s. Sulfadoxine-pyrimethamine followed. Mefloquine resistance emerged in Asia around the time the drug became widely available in the mid-1980s. Artemisinin, currently the frontline treatment in much of the world, is now also showing early signs of resistance in parts of South and Southeast Asia.

"Signs first emerged of chloroquine resistance. We have now noticed artemisinin resistance too. There is a dire need for novel anti-malarial drugs," said Dr Pushkar Sharma of the National Institute of Immunology, Delhi.

This is the context in which the Ark1 discovery carries particular weight. Rather than targeting the parasite's metabolic pathways the way existing drugs do, this research targets the machinery that allows the parasite to reproduce at all.

What the scientists found

Plasmodium uses an unusual method of reproduction called fission, which allows it to produce several thousand copies of itself almost simultaneously. Crucially, it divides differently depending on whether it is inside a human or a mosquito, making it harder to design drugs that work across both stages.

But Ark1 appears to be present and essential in both.

"Studies show Aurora-related Kinase 1, or Ark1, regulates parasite division in humans and mosquitoes," said Dr Sharma.

The scientists found that Ark1 is produced by the parasite at precisely the moment it is needed during cell division. It plays a central role in spindle formation and nuclear division, the process by which the parasite correctly splits its genetic material into new cells. Without it, the division process breaks down.

If a drug could be designed to block or inhibit Ark1, the parasite's ability to multiply could be stopped or severely disrupted.

The microscopy problem, and how Britain solved it

Getting to this finding was not straightforward. The scientists first had to delete Ark1 from the parasite and then observe what happened. The second part turned out to be the harder one.

Plasmodium can be as small as one micron in size. A human hair is 50 to 100 microns thick. Imaging the parasite at that scale, in enough detail to see the impact of Ark1 deletion, was beyond the reach of standard microscopy.

The solution came from the University of Nottingham team, led by Rita Tewari, a molecular parasitologist and professor at the School of Life Sciences.

"We used Ultra Expansion Microscopy, a relatively new technique in malaria research, which involves physical expansion of cells to almost five times their normal size. This let us image the impact of Ark1 deletion," Tewari said.

The technique, which is relatively new to malaria research, allowed the team to see in detail what happened when the control switch was removed.

Five years in the making

The research is the product of an ongoing collaboration between Sharma's group at NII, which has focused on signalling pathways relevant to how the parasite infects and spreads through human red blood cells, and Tewari's group at Nottingham, which has focused on how the parasite divides and develops inside the mosquito host.

"Specifically, we have been working on Aurora kinases like Ark1 for almost five years," Tewari said.

Key contributions came from Annu Nagar, a PhD student in Sharma's group who investigated how Ark1 regulates parasite division during blood-stage development, and from Ryuji Yanase, Mohammed Zeeshan, and others from Tewari's group who worked on the mosquito side. Eelco Tromer of the University of Groningen contributed computational biology and bioinformatics work that was critical in identifying the novel Ark1 complex in the parasite.

The research was funded by a Team Science Grant from the Department of Biotechnology and Wellcome Trust India Alliance, which supported the three-way collaboration between the Sharma, Tewari, and Prasad groups.

What comes next

The scientists are now working to map the broader network of proteins that Ark1 controls, to better understand how the parasite coordinates its unusual mode of division.

"We are trying to figure out the mechanisms via which Ark1 plays such a critical role in parasite biology by using modern approaches in collaboration with Dr Keshav Prasad at NITTE University, Mangaluru," said Dr Sharma.

He added that kinase enzymes, the family to which Ark1 belongs, are well-established targets for drug development across a range of diseases, making them promising candidates for anti-malarial drug design as well.

"Protein and lipid kinases are known to be very druggable targets for various diseases. These enzymes are attractive candidates to target malaria parasites, which is also exemplified by our studies," he said.

A drug based on Ark1 inhibition remains years away from clinical use. But the identification of a target that works across both stages of the parasite's life cycle, in both the human and the mosquito, is the kind of foundational discovery that drug development programmes are built on.

(With TOI inputs)