June 9, 2009

Malaria Researchers Turn to Mosquitoes To Fight Disease

As part of a worldwide push to eradicate one of the oldest and deadliest diseases still in existence, scientists at the University of Maryland are tinkering with mosquito DNA to produce insects capable of carrying a larger than normal load of the parasite responsible for malaria.

Which begs the question: why would they want to produce more infectious mosquitoes?

Scientists say they hope to use the genetically engineered insects to harvest more of the key ingredients needed for the world's first living malaria vaccine.

A malaria vaccine composed of living malaria parasites "was considered laughable five to seven years ago," according to Dr. Stephen Hoffman, CEO of the Maryland-based biotech company Sanaria Inc.  However, if the preliminary results coming out of several labs around the world are accurate, a paradigm-shift may be coming in the way researchers think of malaria treatment.

While working for the U.S. Navy in the 1990s, Dr. Hoffman worked on a project in which malaria-carrying mosquitoes were irradiated in order to weaken the malaria-causing pathogen known as Plasmodium falciparum living in their salivary glands. Hoffman and 13 of his colleagues then allowed these blood-sucking insects to stick them more than 1,000 times.

In typical malaria pathology, the microscopic parasites first race to their victim's liver and rapidly multiply before making their way into the bloodstream where they then begin to wreak havoc on the patient's health. Instead, the weakened parasites used in Hoffman's experiment remained innocuously in the liver, where they were unable to reproduce but still managed to trigger an immune response from the body.

When the 14 scientists later subjected themselves to the bites of mosquitoes carrying the normal, non-weakened form of malaria, all but one of them proved resistant to the disease for at least 10 months after exposure to the irradiated parasites.

For Hoffman's team, the question then became how to convert that temporary immunity into a long-lasting vaccine. According to Hoffman, critics said it couldn't be done. "We were dismissed by 99 percent of the people in the malaria field," he recalls.

Yet two weeks ago, with approval the U.S. Food and Drug Administration's, the first round of 100 U.S. volunteers began receiving test doses of Sanaria's vaccine, in an early-phase safety study.

And Hoffman's group is not the only team of researchers who have begun thinking outside-the-box in terms of malaria treatment.

Dr. David O'Brochta of Maryland University has been hard at work creating another sort of mutant mosquito"”one that has been genetically modified to have its malaria-carrying capacity and ability to infect greatly hindered.

"It's really gene therapy for insects," says O'Brochta, who heads the university's novel laboratory and, with the help of federal funding, is helping to create both the super-infectious breed as well as the non-infectious variety.

It's a change in the philosophical approach to dealing with the disease, and O'Brochta himself is well aware of the possibility that the research could potentially be a dead-end street.

Almost 250 million people contract malaria each year, nearly 1 million of which die from the infection"”the vast majority being young children in Africa.   Currently, bed netting and insecticides are the most commonly used defenses against infection.

In O'Brochta's lab, researcher Robert Harrell gazes fixedly through the lens of a microscope, attempting to stab a mosquito egg with ultra-thin glass needle. He's attempting to inject modified DNA back into the larval parasite in a location that should, with a bit of luck, develop into the insect's reproductive organs.  Thus, when mosquito later reaches adulthood, it will hopefully be able to pass on its new trait to its progeny.

But ensuring that the truncated genes are inherited is no easy task. Of the mutants that survive to adulthood in the lab, only around 2 percent of their offspring actually carry the modified gene.

In the wild, the species of mosquito responsible for spreading malaria has a sort of biological-radar that it uses to find human blood.  O'Brochta says that for the malaria-resistance gene to spread throughout the population, it would have to spread much more quickly and efficiently than it does in the lab.

Facilitating this process has been the main focus of his research.

Back at the Sanaria lab and their quest for the super-infectious mutant mosquito, company entomologist Adam Richman explains that it currently takes roughly 3,000 normal mosquitoes, each one dissected by hand, to make one batch of the experimental vaccine.

Lab workers dip the frozen mosquitoes into a beaker full of alcohol, killing them the insect but not the stunned parasites in their salivary glands. Then, with the help of a microscope, the lab techs delicately pluck each mosquito's head from its body in order extract the tiny, translucent glands.

Sanaria says that their goal is to engineer a mosquito capable of carrying some 200,000 of the young parasites"”more than twice the amount typically found in normal insects. From his university lab, O'Brochta is attempting to create this super-bug by turning off a gene that helps protect the insect when it consumes malaria-infected human blood.

"No one has ever made transgenic mosquitoes with this gene knocked out," he says. "We want to cripple its immune system so when it takes an infected meal, it gets infected at very high levels.


On The Net:

Plasmodium falciparum



University of Maryland