HARVARD GAZETTE ARCHIVES

Dyann Wirth is senior author of the study that offers the first map of genetic diversity of the malaria parasite. This work can rapidly translate to improvements on the ground, such as better diagnosis of specific malaria strains. (Staff photo Jon Chase/Harvard News Office)

Researchers have created the first map of genetic diversity of the malaria parasite, providing new insights in the fight against a public health scourge that kills one person every 30 seconds.

In work that focused on the most deadly of the four malaria parasites that infect humans, Plasmodium falciparum, researchers found nearly double the diversity they expected. They also identified genetic regions linked to resistance to two anti-malarial drugs.

The advance, by an international team led by researchers at the Broad Institute of Harvard and the Massachusetts Institute of Technology (MIT), can rapidly translate to improvements on the ground, such as better diagnosis of specific malaria strains and monitoring for the emergence of drug resistance, according to Dyann Wirth, chair of the Harvard School of Public Health's Department of Immunology and Infectious Diseases, co-director of the Broad Institute's Infectious Disease Initiative, and the study's senior author.

"One of the immediate applications is that we should be able to develop a tool to detect the emergence of drug resistance in populations and map its spread," Wirth said.

The early detection of drug resistance is critical in better managing the disease. If doctors understand early on that a patient is infected with a strain resistant to a particular drug, they can use other medications and strategies to fight the disease, rather than a blind trial-and-error approach.

"This is a way for one to get ahead of the curve, instead of waiting for clinical failure," Wirth said.

The research represents a critical intersection of advancing technology and basic science aimed at understanding the human genome - pioneered under the leadership of Eric Lander at the Broad Institute - and their application to modern public health problems.

"Genomic tools have largely been applied to first-world diseases up to now," said Lander, Broad Institute director and one of the study's authors. "This project underscores the power and importance of applying them to the devastating diseases of the developing world. ... Knowing the enemy will be a crucial step in fighting it."

The research, published online in the journal Nature Genetics, was the result of 15 months' work by 28 different researchers at the Broad Institute, Harvard University, MIT, the Whitehead Institute for Biomedical Research, and Cheikh Anta Diop University in Senegal. Using technology developed during the decoding of the human genome, the work builds on the initial sequencing of the malaria parasite's genome, achieved after five years' effort in 2002.

The current work examined the DNA of more than 50 different malaria parasite specimens from around the world at three levels of resolution. By comparing the different specimens to each other and to the initial 2002 sequence, researchers identified 47,000 changes in the basic units, called bases, which make up the malaria parasite's DNA.

Malaria is one of the world's most deadly diseases, killing 1 million and sickening between 350 million and 500 million annually, according to the World Health Organization. It is transmitted by mosquitoes, which inject people with the malaria parasite when it bites. Malaria victims develop high fever, chills, aches, headaches, vomiting, and other severe, flu-like symptoms. Most of those who die of malaria each year are children living in Africa.

The new genetic map of the disease can be used to trace the geographic distribution of different strains around the world. It can also be an asset to those trying to develop malaria drugs and vaccines, allowing a more systematic approach, according to Sarah Volkman, a research scientist at the Harvard School of Public Health and one of the study's authors.

"It opens a tremendous new door in terms of how we think about designing a new strategy," Volkman said.

Much of the malaria DNA's variation is in areas that affect the proteins on the parasite's surface, Wirth said. The human immune system uses those proteins to recognize the parasite as an invader. Their diversity is a sign of the ongoing arms race between the human immune system and the malaria parasite. By changing its surface proteins, the parasite evades the human immune response, which then adjusts to the new threat, sparking another change in the parasite's surface makeup.

The findings have already begun to affect the thinking of malaria experts about a vaccine. Wirth said the additional genetic diversity discovered may mean that a single vaccine to immunize people from all strains of malaria is unrealistic. With so much diversity, a vaccine that works on one type of malaria may not work on another. She said the best that public health officials may be able to hope for is a vaccine regimen similar to that used with the flu, where vaccines specific to predominant strains are made each year, changing along with the shifting flu virus type.

Though the genetic map of malaria diversity is important, it is just a first step. Researchers who worked on this project are already analyzing new malaria samples, hoping to add to the catalog of genetic diversity, including samples from the Indian subcontinent, which was not included in the initial analysis.

Pardis Sabeti, a postdoctoral fellow at the Broad Institute and one of the paper's authors, said they're working to develop new technology that will allow testing in the field, which will allow the collection and analysis of many, many more samples.

Even with new technology on their side, Wirth predicted the fight against malaria will be a long one. She said gains can be made, but that it is critical that public health officials, policymakers, and the scientific community realize they're in for the long haul.

Victories in the past have been undone by relaxed vigilance, she said, and the nature of the malaria parasite means it has to be 99.99 percent eradicated before attention can be diverted elsewhere. She cited the example of Sri Lanka in the 1960s where a malaria eradication program had the number of cases down to just tens or hundreds a year. Last year, she said, there were about 1 million.

"A single infected person can lead to 100 new infections," Wirth said. "It is fully treatable and fully preventable, but it requires constant attention. We're talking about a decades-long effort, but it will be worth it."