In a double-dollop of bad news for malaria fighters, researchers have discovered the parasite that causes the disease is genetically more diverse, older and better adept at resisting drug treatments than previously thought and therefore may present a greater-than-expected challenge to controlling the deadly scourge that infects up to 500 million humans and kills as many as 3 million each year.
In two reports published in the British journal Nature, researchers from the National Institutes of Health in Bethesda., Md., and the University of Chicago paint a disturbing picture of Plasmodium falciparum, the most lethal of four species of mosquito-borne malaria microorganisms. Once infected through a bloodsucker's bite, the patient faces a lifelong threat of recurrence of the disease, even after successful drug treatment, characterized by fever, chills, headache and sweating and, in the most severe cases, organ failure, coma and even death.
No vaccine is available to prevent spread of the plague, which runs rampant in sub-Saharan Africa and other tropical and sub-tropical parts of the globe, primarily among children under age five. The number of cases of malaria worldwide is increasing, mainly because of the evolution of drug-resistant parasites.
Scientists screening the organism's genetic makeup deemed it well protected against efforts to diffuse its deadly power, underscoring the complexity of the task at hand.
"Although we heard of good vaccines coming so many times in the media, the public and scientists have to be more realistic. We have a very difficult situation to deal with," lead study author Xin-zhuan Su of the Laboratory of Malaria and Vector Research at the National Institute of Allergy and Infectious Diseases told United Press International.
"After 20 years of efforts, we do not have any effective vaccine yet. Parasites resistant to most drugs available today have been reported, except a new Chinese drug (called) Artemisinin, and its derivatives," he added. "New drug developments are urgent. If resistance to Artemisinin occurs, we may not have any good drugs to treat some patients. When we plan for vaccine and drug development, we have to keep in mind we are dealing with complex parasite populations."
Just how complex has been the subject of debate for more than a decade. Scientists have been deliberating the genetic diversity and origin of the parasite since the late 1990s when a group of evolutionary biologists proposed a "Malaria Eve" hypothesis to explain its roots. By examining 10 of its genes, they suggested the bug is relatively young -- perhaps only 3,000 to 5,000 years old -- and genetically similar from place to place. As such, it should not be overly difficult to control.
Su and Jianbing Mu of NIAID, Wen-Hgsiung Li of Chicago and their colleagues at the NIH National Center for Biotechnology Information set out to explore the questions further. In a painstaking search, the team looked for genetic differences among parasites from Southeast Asia, Africa, South America, Central America and Papua New Guinea.
Meticulously sorting through the same 204 genes in each organism and comparing genetic fingerprints, they detected mutations in the five regional strains. Based on this diversity in the genomes, the investigators estimated the earliest common parasite ancestor must have originated 100,000 to 180,000 years ago, about the time humans started coming out of Africa and spreading their wings around the globe.
"We speculate that when the human population grew, the malaria parasite grew with it," Su said.
"This is probably the most tenuous part of the study, and the community knows that these dates need to be interpreted with caution," said molecular biologist and geneticist Andrew Clark of Cornell University in Ithaca, N.Y., who analyzed the findings in an accompanying commentary.
The second study -- a DNA analysis of 87 parasites from patients around the world -- revealed bugs resistant to chloroquine, a former mainstay anti-malaria drug, emerged in several regions and blazed across continents. The finding contrasts with the long-held notion of some scientists that such immunity developed independently in only two areas in the mid-20th century, then gradually crept to other countries. The new information implies invulnerability to therapy can start and spread more pervasively than previously thought and points to the need for careful drug-use monitoring programs, scientists said.
"What is really daunting is that new mutations arise to confer the resistance. They arise all the time," Clark told UPI.
The survey -- marking the first DNA fingerprinting of the entire genome of a complex parasite -- provides the most reliable and powerful such data to date, Su said.
"(Computations and computer simulations) showed very clearly that a large segment of a parasite chromosome had hitchhiked along with the key chloroquine resistance gene," said John Wootton of NCBI, who conducted the analysis. "This is a hallmark, we think, of how chloroquine has ... profoundly influenced recent P. falciparum evolution."
"This study changes our thinking about chloroquine resistance," Su said. "First, it has happened more frequently than we thought. Second, we now know that the African parasite that developed resistance in the late 1970s did not arise independently but came from Southeast Asia."
The resistant parasites spread through the African continent in a mere decade or so, the investigators found.
"This means that when a drug- or vaccine-resistant parasite arises, it will not take long for this resistance to spread to other continents, reflecting human travel, particularly by air, and the high transmission rate via mosquitoes in Africa," Su said.
The scientists think the studies have important implications.
"Thorough knowledge of the genetic diversity of the parasite population is the first defense against this calamity," Clark said. Having an inkling of the difficult road ahead, scientists are already pursuing numerous avenues, exerting efforts to develop drugs and vaccines, to enhance public education, to expand the use of bed nets, insect repellents and insecticides as well as to control malaria by genetic manipulation of the Anopheles mosquito that carries the parasite, he said.
"Malaria is not just a problem of Africa," Clark explained. "It is a problem of humanity, and it is getting worse fast. Given this situation, malaria warrants a considerable increase in effort to find a solution. These studies underscore the need for understanding not only of the genomes, but of variation in those genomes to control this scourge."
