Tagging Essential Malaria Genes to Advance Drug Development
Posted on by Dr. Francis Collins
Caption: Colorized scanning electron micrograph of a blood cell infected with malaria parasites (blue with dots) surrounded by uninfected cells (red).
Credit: National Institute of Allergy and Infectious Diseases, NIH
Credit: National Institute of Allergy and Infectious Diseases, NIH
As a volunteer physician in a small hospital in Nigeria 30 years ago, I was bitten by lots of mosquitoes and soon came down with headache, chills, fever, and muscle aches. It was malaria. Fortunately, the drug available to me then was effective, but I was pretty sick for a few days. Since that time, malarial drug resistance has become steadily more widespread. In fact, the treatment that cured me would be of little use today. Combination drug therapies including artemisinin have been introduced to take the place of the older drugs [1], but experts are concerned the mosquito-borne parasites that cause malaria are showing signs of drug resistance again.
So, researchers have been searching the genome of Plasmodium falciparum, the most-lethal species of the malaria parasite, for potentially better targets for drug or vaccine development. You wouldn’t think such work would be too tough because the genome of P. falciparum was sequenced more than 15 years ago [2]. Yet it’s proven to be a major challenge because the genetic blueprint of this protozoan parasite has an unusual bias towards two nucleotides (adenine and thymine), which makes it difficult to use standard research tools to study the functions of its genes.
Now, using a creative new spin on an old technique, an NIH-funded research team has solved this difficult problem and, for the first time, completely characterized the genes in the P. falciparum genome [3]. Their work identified 2,680 genes essential to P. falciparum’s growth and survival in red blood cells, where it does the most damage in humans. This gene list will serve as an important guide in the years ahead as researchers seek to identify the equivalent of a malarial Achilles heel, and use that to develop new and better ways to fight this deadly tropical disease.
The researchers, including John Adams and Rays Jiang, University of South Florida, Tampa, and Julian Rayner, Wellcome Trust Sanger Institute, United Kingdom, used a genomic strategy that’s been around since the 1980s. It relies on transposons—snippets of DNA sometimes referred to as “jumping genes” for inserting themselves randomly into the genome—to disrupt thousands of genes in the P. falciparum genome. Because the team’s transposons specifically target adenine and thymine, they could capitalize on the very quirk that had made the parasite’s genome hard to study by other means. Once a transposon inserts itself, the gene becomes inactive.
All told, the researchers generated more than 38,000 P. falciparum mutants. That’s pretty impressive when you consider that previous efforts over decades only generated a few hundred mutants.
Those mutants carried transposon-induced disruptions in 2,042 of the parasite’s 5,399 genes. Mutations didn’t appear in the remaining 3,357 genes, including 677 genes that possibly aren’t amenable to mutation with the transposons.
But, the data suggest the mutants for the remaining 2,680 genes are “missing” because those genes are indispensable for P. falciparum’s survival in red blood cells. Without them, those mutants simply die and disappear.
That list of 2,680 essential genes now becomes an important starting point for future research as well as drug and vaccine development. In fact, many of these genes are already targets of current antimalarial drugs, further confirming their therapeutic value. You could think of those as the “positive controls” for this experiment. About 1,000 of the essential genes identified are also conserved among Plasmodium species, offering the extra potential for developing broad-spectrum drugs to treat malaria.
In addition to this valuable list, continued study of the surviving mutants will elucidate other important aspects of P. falciparum’s biology. For example, they will enable critical studies into how the parasite modulates the human immune system and how it responds under the pressures of drug treatment.
Despite the encouraging progress in treatment and prevention, malaria remains a major global health problem. In 2016 alone, an estimated 216 million people were treated for the disease. About 445,000 people died that year from malaria, most young children [5]. While combination treatments reduce the risk of the malarial parasites growing resistant to the front-line drug artemisinin, resistance remains an emerging threat nevertheless. With this new resource in hand, the hope is we can stay ahead of P. falciparum and continue making strides toward the ambitious goal adopted by the World Health Assembly to reduce the global burden of malaria by 90 percent in the decade ahead [6].
References:
[1] Overview of malaria treatment. World Health Organization. 18 January 2018.
[2] Genome sequence of the human malaria parasite Plasmodium falciparum. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B. Nature. 2002 Oct 3;419(6906):498-511.
[3] Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Zhang M, Wang C, Otto TD, Oberstaller J, Liao X, Adapa SR, Udenze K, Bronner IF, Casandra D, Mayho M, Brown J, Li S, Swanson J, Rayner JC, Jiang RHY, Adams JH. Science. 2018 May 4;360(6388).
[4] Transposon-mediated mutagenesis of a baculovirus. Fraser MJ, Brusca JS, Smith GE, Summers MD. Virology. 1985 Sep;145(2):356-361.
[5] Malaria’s impact worldwide. Centers for Disease Control and Prevention.
[6] Global Technical Strategy for Malaria 2016-2030. World Health Organization. May 2015.
Links:
Malaria (National Institute of Allergy and Infectious Diseases/NIH)
John Adams (University of South Florida, Tampa)
Rays Jiang (University of South Florida, Tampa)
Julian Rayner (Wellcome Trust Sanger Institute, United Kingdom)
NIH Support: National Institute of Allergy and Infectious Diseases
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