Malaria is a scourge of humanity. Every year, more than a million people die as a result of the disease.A vaccine remains a distant hope, and resistance to existing drugs is increasing.Researchers at the Bernhard Nocht Institute for Tropical Medicine (BNI) in Hamburg and the Nanyang Technological University (NTU) in Singapore have now succeeded for the first time in comprehensively predicting the function of proteins of the malaria parasite Plasmodium falciparum.To do this, they combined methods from computer science and cell biology.Scientists from around the world working to combat malaria will now be able to access their protein database, published in the journal Nature Biotechnology (January 2010, Vol 2, p. 91-98).  

Every 30 seconds in Africa, a child dies from the effects of "swamp fever". This is in no small part because the parasite that causes the disease is extremely adaptable. "The growing drug resistance of malaria parasites means that the development of new strategies for the prevention and treatment of infection are urgently required", says Tim Gilberger from the Bernhard Nocht Institute for Tropical Medicine in Hamburg. The pathogen goes through a unique life cycle. For Plasmodium falciparum, humans represent only a stopover on a long and tortuous development cycle.

• The infection begins when a person is bitten by an infected Anopheles mosquito. Germs enter the blood with the saliva of the mosquito.
• They then migrate to the liver, where they remain and continue to develop. Eventually, they leave the liver and reenter the bloodstream.
• There, they attack the red blood cells, before multiplying inside, causing them to burst. For the unfortunate patient, this results in a high fever; in advanced stages it causes anemia. The released pathogens then infect other cells, and the process is repeated.
• Some pathogens leave the cycle of infection and propagation, and transform themselves into male and female germ cells.
• The germ cells are picked up again by a mosquito feeding on the blood of the victim, where they migrate into the insect’s gut.
• There, they form a new generation of pathogens. These migrate into the mosquito salivary glands, after which they are retransmitted to humans through a simple bite. The cycle is completed.

Database with more than 2,500 parasite proteins
Researchers hope that this particular approach to reproduction could provide targets for new drugs, by using substances that damage the parasite in its various transformations, but which do not attack the human body. The process of identifying such substances, however, is like looking for a needle in a haystack. A team of scientists headed by Gilberger and his colleague Zbynek Bozdech from Nanyang Technological University (NTU) have now developed a helpful tool for this mammoth task: In a joint project, they have created the worlds largest institution for research, care and education in the field of tropical diseases and emerging infectious diseases.

After around five years of research, the database has finally been published in the January 2010 issue of Nature Biotechnology. The effort has paid off, thinks Gilberger. Because "only the full understanding and characterisation of the genes can represent a significant step in the development of new strategies for the prevention and treatment of malaria," says the parasitologist.

Bioinformatics combined with high-throughput screening
Few scientists to date have attempted an analysis of all the genes of the malaria parasite. The biological specificity of the parasite complicates the research techniques that scientists successfully apply with other organisms. Nevertheless Gilberger and Bozdech took the bold step of gathering data by means of "microarray technology”. This involved using an automated approach to systematically compare the influence of hundreds of different drugs and substances on the genetic regulation of the pathogen.

The researchers were able to combine their own results with developmental information from different malaria pathogens, the analysis of repeating patterns in DNA sequences, and high-throughput investigations on the interaction between individual proteins. "We were only able to create the first reliable model of each network of proteins active in P. falciparum and their interactions by combining four different research methods," says Gilberger. The database is now available for scientists everywhere.

Taking a closer look at invasion proteins
Gilberger is most interested in a group of proteins dubbed "Invasion" by the researchers. This is the sum of all proteins that are - according to the prediction – involved in the malaria parasite’s invasion of the blood cells. The Hamburg-based scientists have already begun investigating 70 potential Invasion proteins for their role in penetrating the cells.

The initial results have been promising, says Gilberger. His group has succeeded in marking as many as 42 proteins with a fluorescent dye, thereby determining the localisation of the protein molecules in the parasite. "Maybe, with appropriate medication, we can prevent the spread of the virus in the blood cells in the future," hopes the BNI parasitologist. Until then, however, much water will flow down the Elbe River. "Only the functional analysis of more than 300 Invasion proteins will allow us to identify the weaknesses in this process," says Gilberg. The knowledge gained could then aid in the development of new preventive and therapeutic approaches against malaria.

Bernhard Nocht Institute
The Bernhard Nocht Institute for Tropical Medicine is Germany's largest institution for research, care and education in the field of tropical diseases and emerging infectious diseases. 
For the BNI website: http://www.bni-hamburg.de/

• Protein database - a new weapon against malaria