Mutation may halt malaria

THE BALTIMORE SUN

Ninety seconds after Anopheles gambiae touches down on naked flesh, the mosquito's bloody deed is done: Her double-barreled proboscis has tapped a tiny vessel, siphoning liquid up one tube while squirting specially-formulated saliva down the other to stop clots.

By the time she lumbers off, three times her weight in blood fills her gut. If the mosquito is careful - and you're lucky - you'll barely know she was there.

But millions of people who get bitten aren't so fortunate, because Anopheles mosquitoes can also harbor a deadly stowaway, the malaria parasite. For more than a century scientists and public health officials have struggled - and failed - to defeat the disease, which ranks alongside AIDS and tuberculosis as one of the world's leading killers.

"The parasite always seems to outsmart us. It's always one step ahead," says Nirbhay Kumar, a researcher at the Johns Hopkins Malaria Institute who works on vaccines for the disease.

But now scientists may finally be getting back in the game.

In a development being described as a major milestone in the war on the disease, researchers at Case Western Reserve University in Cleveland have genetically engineered the first malaria-resistant mosquito.

While the experiment, described today in the journal Nature, was conducted only on mice - and was not always successful in preventing transmission of the parasite - it still got malaria scientists buzzing.

"It's a very significant beginning," says Kumar. And it's just one of many advances on the genetic front malaria researchers are crowing about this year.

In February, scientists announced that after six painstaking years they had cracked the genetic code of Plasmodium falciparum, the most deadly of four species of malaria parasites that infect humans.

This summer, scientists at Celera Genomics in Rockville and at other labs are expected to decode the DNA of Anopheles gambiae, the most common carrier of malaria in Africa, where 90 percent of the deaths from the disease occur.

Once those two sequences are in hand, researchers will possess the genetic codes of all three characters in the deadly drama - man, mosquito and malaria parasite - potentially opening the door to new weapons against the disease.

The genetically-engineered mosquito was created in the laboratory of Marcelo Jacobs-Lorena, a molecular biologist at the Case Western Reserve University in Cleveland.

A former fruit fly researcher, Jacobs-Lorena began working with mosquitoes in the mid-1980s, around the same time that people started talking about genetically altering mosquitoes to stop malaria.

Inside his steamy mosquito menagerie, 6,000 of the insects - essentially syringes with wings - dive-bomb around their cages. Portable space heaters and pans of water placed around the room help jack up the temperature to 80 degrees with 80 percent humidity.

Surprisingly, says Jacobs-Lorena, bug bites are rare. To feed the mosquitoes, his researchers lay anesthetized mice on top of the cages, so the females - the only ones that drink blood - can get the meal they need to produce eggs. Mosquito larvae are fed Friskies Senior, a brand of low-fat cat food. ("I don't know why," says Jacobs-Lorena. "It's just what people do.")

Many of the mosquitoes are Anopheles stephensi, a species that carries malaria in India and the one Jacobs-Lorena and his colleagues used to create mutants. The trick was to find genes that trip up the parasite but leave the mosquito unharmed. If a mosquito is too sick to pass along the mutation, the gene will have no chance of taking root in the wild.

Building on the work of researchers who discovered how to insert foreign genes into mosquitoes, Jacobs-Lorena fished for a target for a genetic attack. After three years he found one: A molecule called SM1, which prevents the parasite from worming its way out of the mosquito's gut.

In the life cycle of the Plasmodium parasite, the gut is an important crossroads, crucial to how malaria is transmitted from one person to another. After several days inside the gut, the parasite makes its way through the lining in a process that remains mysterious. Once outside, the parasite tracks down and invades the mosquito's salivary glands. "Then it just stays put until the mosquito bites somebody," says Jacobs-Lorena.

The researchers created a synthetic gene that produces SM1. Although the scientists still don't know why it works, it appears to prevent the parasite from finding the molecular trap door it uses to escape. "It's blocked right there," says Jacobs-Lorena. Imprisoned inside its host's gut, the parasite is unable to get to the salivary glands - and ultimately people.

However SM1 may not be enough, says Jacobs-Lorena. The gene cut down the number of parasites that escaped the gut by 80 percent and prevented the mosquitoes from infecting mice in two out of three experiments. Some parasites, however, still made it to the salivary glands. And that, scientists say, isn't good enough.

"Our target has to be zero," says Anthony James, a malaria researcher at the University of California in Irvine who figured out how to insert a foreign gene into a mosquito.

If the mosquito was released into the wild, says James, it's possible that parasites resistant to the synthetic gene could crop up - just as many parasites have become resistant to drugs used to prevent the disease.

Jacobs-Lorena and others are hunting for other genetic targets - all of which need to be tested on humans. (The parasite Jacobs-Lorena used in his experiments infects only rodents.)

And that won't be the end of their problems. Once you have a malaria-resistant mosquito, the next question is: How do you get it to spread the gene in the wild?

The problem raises both scientific and ethical issues.

After witnessing public concern over corn, tomatoes and other genetically engineered crops in recent years, malaria researchers are being extra-cautious about how they describe plans for a mutant mosquito.

"We clearly do not have enough information to make it a risk worth taking at this point," says James.

One worry is that a genetically engineered mosquito may no longer be able to carry malaria, but might become a better carrier for other diseases, such as yellow fever or West Nile virus.

And even when a mutant mosquito is deemed safe, there's no guarantee it will take hold in the wild. One possible approach, says James, would be to spray DDT or some other insecticide to wipe out most of a resident mosquito population, then release as many malaria-resistant mosquitoes as possible.

But with 60 different species of mosquitoes capable of carrying the disease, it's unclear whether it would mean creating a mutant for each species.

"There's clearly a lot of work still left to do," says James.

For now, he says, the enemy is just a little too clever.

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