Battling an Ancient Scourge in the Laboratory, the Field and the Classroom

The Harvard Malaria Initiative is an epicenter of hope in the global battle against malaria. Led by Dyann Wirth of the Department of Immunology and Infectious Diseases at the Harvard School of Public Health (HSPH), the Initiative's world-class faculty collaborates with leading scientists throughout Harvard's medical community as well as with research colleagues in developing nations plagued by the disease, which now claims over two million lives a year. Research made possible by the recent decoding of the malarial parasite genome is enabling Initiative researchers to explore new potential drugs and drug targets desperately needed to overcome the parasites' growing resistance to all known therapies. Building on connections established in eight countries on three continents by HSPH and the world-renowned Harvard AIDS Institute, the Harvard Malaria Initiative has the ability to work shoulder-to-shoulder with a growing number of trained experts in Africa and Asia, who are themselves in the best position to provide sustainable aid to adults and children throughout their home countries.

The Initiative's mission is pragmatic and goal-directed. Its aim is to generate research findings that can be put to work to save lives, alleviate suffering, and prevent the further spread of disease among the world's hardest hit populations.

Launching a new plan of attack

Over the past several years a resurgence of malaria has overwhelmed the medical world's ability to fight the disease. While the best longterm hope against malaria may rest with a preventive vaccine, efforts at vaccine development have so far been unsuccessful, leaving drugs as the only means of treatment available. But the mosquito-borne parasite that causes malaria - Plasmodium Falciparum - is rapidly becoming resistant to all known drugs. In response, HSPH launched the Harvard Malaria Initiative in 1997, with the goal of discovering entirely new classes of drugs to control the disease.

Directed by Dr. Dyann Wirth, Professor of Infectious Diseases and a world-recognized authority on tropical diseases, the Initiative builds on two decades of Dr. Wirth's laboratory investigations of mechanisms used by the parasite to resist anti-malaria drugs before the organism itself suffers harm. The program received a major boost in 2001 with a $1 million grant from ExxonMobil. These funds strengthened the Initiative's research capabilities and trained many scientists from countries ravaged by the malaria epidemic.

By 2002, the complete genomic sequence of P. falciparum was mapped, offering new vantage points by which to study its resistance to drugs. In the fall of that year, Dr. Wirth published two papers in the prestigious journals Nature and Science, reporting that the parasite's genetic variability facilitates its transmission from mosquito vector to human host, presenting a major obstacle to the parasite's control. Dr. Wirth and colleagues identified the ends of chromosome 2 as the regions where most of these genetic variations are concentrated. Their genomic studies have opened up unprecedented opportunities for identifying candidate genes for drug and vaccine development.

Multiple research strategies

Dr. Wirth and colleagues are conducting research both in the laboratory and in the field in Africa, where scientists can look in detail at how the parasite mutates under different conditions, in different human populations, under drug treatment, and in the presence of candidate vaccines. She and her colleagues are also looking at the genetics of host-parasite interactions, another arena ripe for study.

Of the 6,000 genes in P. falciparum, an estimated 1,000 are potential drug targets. Current antimalarial drugs are all closely related to one another and target similar pathways, limiting their effectiveness when drug resistance develops. On the other hand, with so many potential drug targets worthy of further study, there is an unprecedented opportunity to identify new chemicals that work on these targets and can serve as the basis for new treatments.  One of the Harvard Malaria Initiative's challenges is to identify which targets offer the best chance for neutralizing or killing the parasite while avoiding drug resistance. These and other studies are carried out collaboratively within HSPH and the broader Harvard community, involving both the Faculty of Arts and Sciences and the Institute of Chemistry and Cell Biology. Using a "chemical genetics" approach, these researchers are working to identify small, synthetic molecules that might serve as the basis for effective drugs that can modulate biological processes and serve as new lead compounds for drug development.

Given malaria's complexity, Dr. Wirth believes that multiple, simultaneous interventions will be needed, and that combinations of new antimalarial drugs will be necessary to overcome the parasite's resistance. Other ways of controlling malaria will need to be used in tandem, she says, from disseminating insecticide-treated bed nets widely, to developing new insecticides, to creating genetically engineered mosquitoes that would breed and thrive in the wild yet be incapable of transmitting the malarial parasite.