Researchers Decode Genetic Secrets of Malaria Parasite

January 24, 2002
By Gautam Naik
The Wall Street Journal

New York - Secrets of the malaria parasite, one of the planet's biggest killers, have long remained hidden in its intricate genetic code. But now it is about to be broken.

After a Þve-year effort, scientists from Britain's Wellcome Trust, the Institute for Genome Research in the US and Stanford University in the US are close to publishing the entire DNA sequence of the malaria parasite. The achievement could turn the tide against a disease that infects about 300 million people annually and kills at least 1.5 million.

The parasite that causes the disease's lethal form, Plasmodium falciparum, has become more dangerous by growing resistant to existing medicines. Yet Western pharmaceutical companies, unhappy at the low proÞts they can garner in poor countries, have largely abandoned research into new malaria drugs.

By scrutinizing falciparum's 30 million letters of DNA code and its 6,000 genes, scientists hope to expose new vulnerabilities in the parasite. Details of the genome are expected to be published in a scientiÞc journal within the next few monthsÑthe researchers wonÕt say which oneÑalthough much of the data are already available free via the Internet.

The genome approach could signiÞcantly reduce the cost of Þnding a new malaria drug. Companies typically spend as much as $800 million to develop a drug using conventional methods. By comparison, the malaria sequencing projectÑthough just a Þrst stepÑcost $30 million.

'The genome will speed things up a lot and have a major impact on drug discovery,'Robert Ridley, a researcher at Medicines for Malaria, predicts. This is a nonprofit group backed by the World Health Organization, the World Bank, the Rockefeller Foundation, the Bill & Melinda Gates Foundation and others.

Some progress has already been made. Jomaa Pharmaka, a tiny pharmaceuticals company in Giessen, Germany, spent four fruitless years trying to locate a protein in falciparum called the "immune modulator," which lets the parasite manipulate the human immune system and thereby survive in the body. The Jomaa scientists already knew the enzymes associated with a similar immune modulator in e coli, a common bacterium. After analyzing the genome data, they found matching enzymes in falciparum. By searching the published literature they then discovered that an antibiotic called fosmidomycinÑa failed drug from the 1970s developed for another purposeÑinhibited the enzymes.

Last year, Jomaa used fosmidomycin in clinical trials, monitored by the WHO, in Gabon and Thailand. According to the company, malaria-stricken patients who took the drug were cured within seven days. It expects to publish the results soon, although a lot more tests are needed before the drug can be marketed.

Genetic clues are especially crucial to understanding malaria's complex life cycle, which makes it such a diffcult foe. At each stage of the bug's lifeÑwhen it exists in the mosquito, sits in a person's liver or lives in the blood cells malaria's genes produce different proteins. Thus, to kill malaria, a drug must target different proteins at different stages, a tricky business. Without a genetic map, that is very diffcult to do.

The free genome data are especially valuable to researchers in developing countries who have a far keener desire to quell
malaria.

Because many developing-world scientists lack high-speed Internet links, the WHO has mailed out thousands of compact discs loaded with the data. The Geneva-based agency has also set up genome training centers in Brazil, India and South Africa.
"Malaria is our disease. We want to train Africans to use the genome," says Winston Hide, a genomics specialist who leads the WHO-supported National Bioinformatics Institute at the University of Western Cape in Cape Town, South Africa. A group of students led by Hide devised a software program that has discovered about 1,000 genes in the malaria sequence.

Five years ago, the falciparum code seemed very tough to crack. The parasite didn't grow easily in a lab, and its code was at least 10 times as big as that of common bacteria. "People said it was impossible" to sequence falciparum, says Neil Hall, a scientist involved in the effort at Wellcome Trust's Sanger Center.

The project was accomplished via an unusual collaboration among scientists, who typically prefer to race one another for glory and gain. Around the same time as Sanger was dreaming up its plan, a similar effort was started by the Institute for Genome Research in Maryland, or TIGR. The nonprofit group was then run by Craig Venter, the brash and ambitious U.S. scientist who now runs the genomics company Celera Corp. Aware of the enormity of the sequencing task, the U.K. and U.S. sides decided to join forces in mid-1996.

Sanger got half of the project, while the other half was given to TIGR, and, to a smaller extent, Stanford University in California. The U.S. team was funded by the U.S. army and navy, which are keen to protect troops posted to malaria-infested regions, the U.S. National Institutes of Health and the Burroughs Wellcome Fund. Mr. Venter's role lasted until 1998, when he left to start Celera and crack the human genome.

Today, work on the malaria genome is nearly complete. "We've been trying to attack falciparum without knowing its details," says Steve Hoffman, a former U.S. navy malaria specialist who is now at Celera. "By sequencing its genome we can now truly understand what weÕre up against."