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The Forever Enemy
August 27, 2009  |  by Michael Anft

(page 3 of 4)

Hidden in small, climate-controlled rooms behind double doors set deep within the fourth floor of the Bloomberg School of Public Health wait tens of thousands of larvae, pupae, and flying bugs. Though hardly the most visited place in the building, the seven rooms here are alive with the kind of activity that makes skin crawl. Christopher Kizito, along with a handful of postgrad students from various labs, “make” 10,000 A. gambiae and its malarial Asian cousin, A. stephensi, each week. If human and animal blood are the keys to the development of successive generations of mosquitoes, then the operation run by Kizito—not quite a rhyme with “mosquito”—is the lifeblood of Johns Hopkins malariologists. Among Kizito’s duties are growing larvae and making sure the mosquito’s talents as a disease vector play out. “We’re here to make sure that researchers can re-create the disease and examine it safely,” says Kizito, a research specialist and a native of malaria-racked Uganda.

The 3,000-square-foot insectary is one of the largest operations of its kind in the world. It provides researchers with the space to develop cultures, breed certain strains of genetically modified insects, and dissect malaria carriers to investigate how parasites live and breed in what researchers call the “midgut” of the mosquito. One of those parasites, the dreaded Plasmodium falciparum, has a home here, too: Behind a series of tightly secured doors, Kizito and crew grow them in square, glassed-in boxes. Candles keep oxygen levels low enough that the parasites reproduce. Once they’re hatched, they are grown in flasks filled with human serum.

Racks with trays of water and mosquito larvae—dots with tails that look like tiny tadpoles—line the walls. Small bits of brown dissolve slowly in the water. “Friskies,” explains Marcelo Jacobs-Lorena, a professor of molecular microbiology and immunology at the School of Public Health. “Other insectaries use tropical fish food, which they’ll grind down and toss in. But we’ve found that cat food works just as well. We don’t even have to grind it—just throw it in there.” Once larvae develop into pupae—basically, bug babies that begin to sprout wings—they are transferred to one-foot-square, mesh-topped enclosures where they will soon begin to breed.

Jacobs-Lorena uses the lab to test his ideas for stopping the parasite’s reproduction. He and his team dissect adult mosquitoes, scooping out salivary glands and viscera for microscopic inspection. Like higher animals, mosquitoes harbor bacteria in their digestive systems. The numbers of bacteria increase after a “blood meal”—the macabre term scientists use to describe a prenatal feast. Finding a way to use that bacteria, or engineer a new type, to block Plasmodium falciparum’s reproductive capabilities would bring the malaria transmission cycle to a halt. Or, preventing newly hatched parasites from leaving the gut and migrating to a mosquito’s salivary glands would scotch it as well.

By tapping the secrets of mosquito bacteria and proteins, Jacobs-Lorena is trying to devise ways to make genetically modified mosquitoes that, when let loose in Africa, would breed with malaria carriers and weaken their diseaseenabling genes. Theoretically, at least, they would breed malaria out of the vector over time.

Jacobs-Lorena’s work over the past 18 years—he came to Johns Hopkins in 2003—has centered on the testing of “phages,” the viruses that infect and destroy bacteria. He and his lab team injected mosquitoes with a complex mix of phages, each covered with a different peptide—a unique sequence of amino acid residues—hoping to find one that would stop Plasmodium reproduction. After injection, they dissected the salivary glands to see which phages took root there. The scientists were especially interested in the phages that contain a particular peptide that keeps the parasite out of the mosquito’s salivary glands. Of the billions of peptides in the phage mixture, the lab team found one that matched their specs. It was find-a-needle-in-the-haystack science, but it worked. “We actually discovered one that would also work in the midgut to keep the parasite from breaking out of it,” Jacobs-Lorena says. “We got lucky.”

The lab’s next step is to engineer bacteria that make the reproduction-halting peptide and then introduce bacteria into mosquitoes in the field. The question is how. “Lab mosquitoes aren’t well-suited to the wild. It will take us another decade or so to learn how to drive genes into a mosquito so that some of these approaches can work,” Jacobs-Lorena says. “The big challenge for us is, How do you spread bacteria amid a wild mosquito population?”

Jacobs-Lorena’s desire to instigate gene warfare between mosquito types is shared by George Dimopoulos, an associate professor of molecular microbiology and immunology at the School of Public Health. But Dimopoulos’ tack is different. He hopes that by tweaking genes that direct a mosquito’s immune system, his research group can prevent the development of recurring generations of the ever-mutating Plasmodium. Theoretically, a new malaria-resistant mosquito could breed with one carrying the disease and spread its resistance to a new generation.

Dimopoulos investigates a mosquito’s immune pathway— the track through which it secretes proteins that fight invasive pathogens. That pathway is controlled by another protein that keeps it locked. It opens only when the system feels the mosquito is threatened. Mosquitoes infected with Plasmodium activate their immune systems to do battle but don’t finish the war—not all of the parasites are killed. The mosquito will always carry a small level of infection, though not enough to make it sick.

Dimopoulos’ lab isolated 10 genes that create immune system proteins (out of a total of 16,000 genes) and used new technologies to turn them on or off. “We thought we could manipulate the mosquito’s immune system so that it develops resistance to the parasite,” Dimopoulos says. “We wanted to see if we could ramp it up before infection.”

In the insectary, Dimopoulos and his lab mates use mosquitoes that start off as healthy, non-infected ones. They jumpstart their immune genes by using a technique called RNA interference, which depletes the protein that locks the pathway to the immune system, allowing disease-killing proteins to flow. Then they feed the insects Plasmodiumladen blood, the caged mosquitoes poking their proboscises through a stretchable Saran Wrap–like plastic to reach a pouch of it. After seven days of observing a mosquito, lab workers open up its insides and search for signs of parasites, comparing it to a control group. Mosquitoes that have had their immune systems boosted show little, if any, signs of the parasite.

“We don’t know the exact mechanism yet, but we know it works to kill the Plasmodium,” Dimopoulos says. “The infection doesn’t affect the health or longevity of the mosquito, which is helpful if you want to spread genetically modified mosquitoes throughout Africa.” Within the next five years, he plans to field-test the immune system–enhanced mosquitoes under very controlled conditions and in huge cages that mimic the African environment. If all goes well, the mosquitoes might be let loose on some small, inhabited islands off the African coast, finally leading to possible trials on the continent in a decade or so.

But introducing mosquitoes with engineered functions into environments already teeming with insects is a huge— and perhaps dangerous—step. Having them breed with malaria-vector mosquitoes might create new generations of bugs that are malaria-resistant, but might also lead them to carry other types of harmful pathogens. Those future generations might not be as hardy in the bush, which would mean they would fail in their mission to breed malaria out of the mosquito. And, Dimopoulos adds, with 20 different malaria-transmitting mosquito species in Africa and 40 worldwide, “it may not be possible to manipulate the genes of all of them.”

Even with those risks, Dimopoulos says, genetically modified insects should be used if they demonstrate a malaria-fighting effect. “It’s not like we’re creating a new mosquito—some monster of some kind. We’re using its own biology to ramp up its immune systems,” he says. “Besides, the skeptics should take note of what we’re up against. More than 400 million people contract malaria each year. What could we do that’s worse than that?”



4 Comments


  1. N. Adlai A. DePano

    Certainly an eye-opener for me. Coming from a country (the Philippines) where malaria has done its share of ravaging, I ironically knew close to nothing about this enduring disease. Thank you for an educational and engaging read.

    One thing though, I believe St. Matthew predates Dickens in stating “The poor you will always have with you …” (Matthew 26:11, NIV).

    N. Adlai A. DePano, MSE ’83, PhD ’87

  2. This is the first two paragraphs of a July 2007 National Geographic cover story. The introductions are strikingly similar:

    It begins with a bite, a painless bite. The mosquito comes in the night, alights on an exposed patch of flesh, and assumes the hunched, head-lowered posture of a sprinter in the starting blocks. Then she plunges her stiletto mouthparts into the skin.

    The mosquito has long, filament-thin legs and dappled wings; she’s of the genus Anopheles, the only insect capable of harboring the human malaria parasite. And she’s definitely a she: Male mosquitoes have no interest in blood, while females depend on protein-rich hemoglobin to nourish their eggs. A mosquito’s proboscis appears spike-solid, but it’s actually a sheath of separate tools—cutting blades and a feeding tube powered by two tiny pumps. She drills through the epidermis, then through a thin layer of fat, then into the network of blood-filled micro-capillaries. She starts to drink.

    Note from the editor: The editors of Johns Hopkins Magazine knew prior to publication of the resemblance between the magazine’s story and National Geographic’s piece. Anytime such a similarity occurs, editors are obligated to examine the matter, and after conferring with writer Michael Anft, we were satisfied that the parallels were unintentional and did not pose a problem. Two experienced and talented writers, reporting on the same disease, independently saw the same storytelling possibilities, which led to similar openings to both stories. We elected not to rewrite our story because we thought it was a fine piece that would stand on its own merits. We appreciate our readers’ sharp eyes and attentive reading. – Catherine Pierre

Trackbacks

  1. Johns Hopkins Magazine – Letters: Winter 2009-10
  2. Johns Hopkins Magazine – Editor’s Note: Boom!

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