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Why Most Malaria Drug Targets Fail: The Surprising Truth About ‘Essential’ Genes
Last Updated: August 7, 2025
The Scientific Arms Race: Hunting for Malaria’s Weak Spots
Malaria parasites are masters of survival, constantly evolving to resist our best drugs. This forces scientists into a relentless arms race, searching for new, vulnerable targets within the parasite’s complex biology. “The current challenges in controlling malaria include emergence of drug resistant parasites and the insecticide resistant mosquitoes” (p. 111). To win this fight, we can’t just keep using old strategies; we must find novel ways to disrupt the parasite’s life cycle.
One of the most promising frontiers is developing drugs that block malaria transmission from humans back to mosquitoes, effectively containing the disease. This post explores the challenging world of identifying new malaria drug targets, using a fascinating case study from Dr. Surendra Kumar Kolli’s doctoral thesis to reveal a surprising truth: not every promising gene is the silver bullet we hope for.
The Urgent Need for New Transmission-Blocking Drugs
Most antimalarial drugs attack the parasite during its asexual stage in the human bloodstream, which is when a person feels sick. However, “these antimalarials have little or no effect on the gametocyte stages of the parasite. The gametocytes are the only stages that are responsible for the parasite transmission from vertebrate host to mosquito” (p. 111).
These gametocytes, the parasite’s sexual forms, can circulate in a person’s blood for weeks, even after they’ve recovered from the illness (p. 111). This makes them a reservoir for infection, allowing the disease to spread. Therefore, finding drugs that specifically target and kill gametocytes is a critical goal for malaria eradication. This is the core mission of organizations like the Medicines for Malaria Venture (MMV), which focuses on discovering the next generation of antimalarial drugs.
The ‘Most Wanted’ List: Identifying a Promising Candidate
With the complete genetic map of Plasmodium available, scientists can hunt for genes that are active during the crucial transmission stages. The parasite’s genome, however, is full of mysteries. “Complete genome sequence of Plasmodium was done in 2002… and nearly 2175 genes still remain unannotated” (p. 114). These “hypothetical proteins” are genes whose functions are completely unknown.
In this study, one such gene stood out: PBANKA_141700. It was a prime suspect for being a critical malaria drug target for several reasons:
- High Expression: Its genetic transcript was found at a “high frequency in RNA sequencing data of gametocyte stages” (p. 114).
- Confirmed Presence: The actual protein was detected in the parasite’s developmental stages within the mosquito (p. 114).
- Uniqueness: “Blast search revealed that the orthologues of PBANKA_141700 were unique to Plasmodium and not present in other species… [and] did not reveal any conserved domains” (p. 115).
This unique profile made PBANKA_141700 a highly interesting candidate. A gene that is highly active during transmission and unique to the parasite is, theoretically, an ideal target for a drug that would harm the parasite but not the human host.
The Experiment: Using Reverse Genetics to Test Gene Function
To determine the protein’s role, the researchers used a powerful “reverse genetics approach” (p. 115). Instead of observing a trait and looking for the gene that causes it (classical genetics), they did the opposite: they disrupted the gene to see what would happen to the parasite.
“We disrupted the promoter of PBANKA_141700 by inserting mCherry and TgDHFR cassettes… and analysed the phenotype of PBANKA_141700 promoter disrupted (PD) parasites” (p. 115). By knocking out the gene’s “on” switch, they could observe if the parasite could still complete its life cycle. If the parasite failed at any stage—blood, mosquito, or liver—it would confirm the gene was essential and thus a valid drug target.
The Surprising Result: A ‘Dispensable’ Gene
The research team put the genetically modified parasites through their paces, testing their ability to develop in mice and mosquitoes. The results were completely unexpected.
“Surprisingly, the disruption of this locus had no effect on parasite development in the mouse or in mosquito suggesting that the product encoded by PBANKA_141700 was not essential for parasite life cycle” (p. 115).
The genetically modified parasites:
- Multiplied normally in the blood of mice (p. 127).
- Developed into oocysts and sporozoites inside mosquitoes just like normal parasites (p. 128).
- Successfully infected liver cells and completed the liver stage of development (p. 129).
Despite being highly expressed and unique, the gene was completely dispensable. The parasite didn’t need it to survive or transmit.
What This Means for Future Malaria Research
This “negative” result is incredibly valuable for the scientific community. It highlights a critical challenge in the drug discovery process.
“Though we could not demonstrate any significant role of PBANKA_141700 in transmission stages, nonetheless an important outcome of this investigation was the lack of correlation between abundance of gene expression… and complete lack of function for the encoded product” (p. 132).
This finding serves as a cautionary tale: just because a gene is highly active doesn’t automatically make it a good drug target. It emphasizes that “a thorough investigation of upregulated genes… must precede prioritisation of valid targets for drug or vaccine development” (p. 132). However, there is a silver lining. Since the PBANKA_141700 gene can be removed without harming the parasite, its location in the genome becomes a safe place to insert other genes for experimental purposes, making it a “dispensable locus… [that] can be utilised for expression of stable transgenes” (p. 132).
Conclusion
The hunt for new malaria drug targets is a complex process of meticulous investigation and, often, the elimination of promising but ultimately non-essential candidates. The story of PBANKA_141700 is a perfect example of the scientific method in action, demonstrating that even surprising, negative results are a step forward. This rigorous work saves time and resources, allowing the scientific community to focus on targets that are truly essential to the malaria parasite’s survival.
Author Bio
This summary is based on the doctoral research of Surendra Kumar Kolli, submitted to the Department of Animal Biology at the University of Hyderabad. His work provides critical insights into the molecular mechanisms governing the Plasmodium parasite’s life cycle.
Source & Citations
- Thesis Title: Investigating the role of Circumsporozoite protein in Plasmodium berghei (Pb) mosquito stages using FLP/FRT conditional mutagenesis system & Functional characterization of Pb K+ channel/Adenylyl cyclase α and a conserved protein PBANKA_141700 by reverse genetics approach
- Researcher: Surendra Kumar Kolli
- Guide (Supervisor): Dr. Kota Arun Kumar
- University: University of Hyderabad, Hyderabad, India
- Year of Compilation: 2016
- Excerpt Page Numbers: 111, 112, 114, 115, 127, 128, 129, 130, 132
Disclaimer: Some sentences have been lightly edited for SEO and readability. For the full, original research, please refer to the complete thesis PDF linked in the section above.
What do you think is the biggest hurdle in developing new medicines for complex diseases like malaria? Share your perspective in the comments!
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