Halting malaria in its tracks; Mosquitoes: Scientists are turning to genetic engineering to make it impossible for the carrier of the disease that kills millions to infect new victims.

THE BALTIMORE SUN

Odd as it may seem, a team of scientists is struggling mightily to keep a special gang of mosquitoes alive and zinging.

Most of us are quite pleased, thank you, to squash any mosquito that sneaks within range, but Barry Beaty's genetically engineered skeeters are very much worth keeping alive. They are part of an experiment to see whether the mosquito's ability to transmit diseases can be erased.

If this and other experiments succeed, the spread of major ailments such as malaria, yellow fever and dengue someday might be reduced or even ended. Every year, millions of people, especially in tropical regions, die of mosquito-borne diseases.

Scientists have succeeded in sneaking a few genes in among the mosquito's existing genes, a feat achieved by biologist Anthony James at the University of California in Irvine.

"We did get over the first hurdle," James says. "We found a couple of ways to get genes into the bugs, and they are stable and inheritable. We've got proof-of-principle that you can get the genes in."

One of the first genes James inserted changes the mosquito's eye color, which makes it easy to tell whether the gene has been accepted and is working properly. Now Beaty, working with the manipulated mosquitoes at Colorado State University, is attempting to use James' finding to insert "anti-sense" genes designed to stop the dengue virus from getting through the mosquito.

He has had trouble keeping alive the "highly inbred strain" of mosquitoes he is using to prove that new genes can interfere with disease transmission. The next step, Beaty says, is to interrupt disease transmission in mosquitoes that will survive and breed.

Over the long run, James is most interested in overcoming malaria; Beaty is working on three viral diseases -- yellow fever, dengue (also called breakbone fever) and La Crosse encephalitis.

The experiments are important, experts say, because the constant battle against mosquito-borne diseases is not being won. Although pesticides provided early success after World War II, mosquitoes have since evolved resistance to many of the poisons, while other toxins turned out to be too harmful for the natural environment.

Along with rebounding mosquito populations, the diseases have also resurged. Health officials estimate that malaria strikes between 300 million and 500 million people annually, almost solely in tropical regions, causing as many as 2.7 million deaths. About 200,000 people are infected with yellow fever annually, leading to 30,000 deaths. And dengue hits about 50 million people every year, and as many as 15 percent of the patients die if not treated.

As the power of insecticides has waned, James says, "we don't really have a lot of weapons" left for the battle, which means "we may run out of control techniques. So we want to contribute to the next generation of control measures, and one proposal is to use genetic control."

The genetic-engineering idea seems feasible because the viruses and protozoans that cause these diseases depend wholly on insects to get from person to person. In malaria, for example, soon after the mosquito takes a blood meal from an infected person, the parasites drawn in with the blood migrate through the mosquito's gut and eventually reach its salivary glands.

New infections occur because the mosquito's saliva -- which acts as an anti-coagulant to keep blood from clotting -- is first injected into the next victim, carrying parasites with it, before the mosquito begins drawing out new blood.

A similar process, with various viruses, occurs in yellow fever, dengue and La Crosse encephalitis, except that the viruses actually infect cells in the mosquito. Many other diseases are transmitted by the bites of other bugs, such as Lyme disease from deer ticks, Chaga's disease from the "kissing bug" in South America, and African sleeping sickness from the tsetse fly.

Thus, if mosquitoes can be altered to make them unable to transmit diseases, the same approach might be tried on the other bugs that are dangerous. The whole idea resembles closing a door through which the germs must travel.

James says new approaches to disease control are needed because "history shows that eradication [of the insects] just isn't going to work. We've dumped tons of toxic agents into the environment, and the mosquitoes are still there."

The idea that mosquitoes might somehow be altered genetically to keep them from spreading disease arose in the 1960s from Chris F. Curtis at the London School of Hygiene and Tropical Medicine.

Curtis "proposed that malaria could be stopped in its tracks if a way could be found genetically to convert its carrier, the Anopheles mosquito, to a form incapable of transmitting the Plasmodium protozoan," which causes the disease, David O'Brochta and Peter Atkinson wrote recently in Scientific American.

The idea gained strength when it was discovered that some mosquitoes are naturally resistant, unable to transmit such diseases. This showed that natural, inborn resistance exists, raising hopes that it might be transferable into the mosquitoes that can carry disease.

"Curtis' proposal was impossible to implement at the time," because new tools of biotechnology hadn't been invented, O'Brochta and Atkinson explained. "But it soon may be realistic, thanks to modern genetic technologies."

O'Brochta is at the University of Maryland Biotechnology Institute. Atkinson is at the University of California in Riverside. Both have extensively studied the transmission of diseases by mosquitoes and other bugs.

Compared to the viral diseases such as yellow fever and dengue, malaria "is a more elusive target," James says. Unlike the viruses, the malaria organism doesn't enter the mosquito's cells but moves through the mosquito after having been picked up from someone's blood. "It's a moving target" that develops, and changes, within the mosquito.

James' team is using chickens in experiments aimed at creating malaria-resistant mosquitoes. "If we can show proof-of-principle for making the mosquitoes, then it will be worth arguing for resources to work with the human parasite."

He adds that "within two years or so we hope to have a malaria-resistant mosquito built" that could have real impact on human disease.

The idea of tinkering with the genetics of mosquitoes has not met with universal enthusiasm. Some critics fear doing anything to alter bugs that would be turned loose in the environment. Others worry that success at blocking the debilitating tropical diseases would exacerbate the problem of human overpopulation.

"People have written to say that it's great science but a horrible idea, because they think it will lead to unchecked population growth," James says. He is going ahead, but carefully.

"The research has to be very well done," James says, and it will be completely open for comment and criticism.

"It's there for everyone to scrutinize and comment on."

Pub Date: 1/30/99

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