BY BRIAN W. SIMPSON
PHOTOS BY MARK LEE

With new insight and a new Institute, researchers are working to extract the malaria parasite from its eternal reservoir — mankind

The female Anopheles mosquito, hungry for blood, lands on a patch of warm human skin.

She plants four of her six hairy legs as she dips her head and thorax. She probes with her long, tube-like proboscis, bending back her labium, the lip that sheathes the proboscis. At the end of the proboscis, knife-like stylets move rapidly like electric carving knives to split the skin. She gently jabs at different angles in the hole until she nicks an arteriole that spouts a subcutaneous pool of blood that she can draw from. Exquisitely evolved, the female vampire will squirt into the cut a small amount of saliva full of anticoagulants to prevent the blood from clotting, according to Mosquito: A Natural History of Our Most Persistent and Deadly Foe by Andrew Spielman, ScD '56, and Michael D'Antonio.

Within a couple minutes, her translucent belly bloats and shifts from waxy gray to cherry red. She sucks a few micrograms of blood — more than her own body weight. Unlike other mosquitoes, the female Anopheles doesn't wait until after feeding to start the digestion process. She excretes water from the blood as she feeds. This allows her to pack into her stomach more of the blood's protein while getting rid of what she doesn't need. She lifts in a slow, tottering flight and moves to a nearby vertical surface. There, sluggish from gorging the blood meal, she continues digesting the blood that will provide the nutrients and proteins necessary for her eggs to develop.

In her blood meal, she has ingested red blood cells, white blood cells, platelets, and other constituents of human blood. And she sucked up something else as well: some protozoan stowaways.

The mosquito, in a simple act essential for reproduction, ensures the reproduction and spread of another species: the Plasmodium parasite.

The malaria cycle begins once more.

By any calculation, malaria's presence and impact are epic. Its domain covers the globe like a ragged shroud, reaching across Africa, India, Southeast Asia, and South America. It exacts a monstrous toll on humanity: 300 to 500 million infections per year and 1.5 to 3 million deaths (mostly of small children). Malaria remains a constant threat to more than 40 percent of the world's population.

A tireless migrant, stealthy invader, rapid reproducer, and constantly evolving organism, the Plasmodium parasite that causes malaria passes through multiple stages in its blood-borne journey from human host through the mosquito to the next human victim. In its earliest stage in the human body, only a handful of parasites are present. Within weeks, the parasite teems by the billions. At each stage, it leaves itself open to potential vaccines or drug treatments, almost taunting researchers with a multitude of options for them to strike. "It's a moving target," acknowledges David Sullivan, MD, an assistant professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI). But he is optimistic. In the parasite's constant shape-shifting from one life cycle stage to the next, Sullivan sees a "series of Achilles heels."

The School's announcement in May of an anonymous $100 million gift to fund the Johns Hopkins Malaria Research Institute (see sidebar) has refocused attention on the ancient scourge and infused the long battle against the parasite with new energy. The nascent Institute joins the front ranks of organizations devoted to stopping malaria, including the London School of Hygiene and Tropical Medicine, the National Institutes of Health, and the U.S. Army and Navy. The momentum added by the Institute comes at a fortuitous time. In recent decades malaria has roared back as the parasite developed resistance to once-powerful drugs like chloroquine, and the Anopheles mosquito similarly acquired resistance to insecticides in some areas.

"If there's no insecticide we can use safely and effectively, and there's no drug we can use safely and effectively, then what can we do? At this point we're helpless really," says Nirbhay Kumar, PhD, an MMI professor.

A vaccine, the magic bullet of malaria research, seems to be the best answer, but remains fiendishly elusive for researchers. Summing up the situation that researchers face, a colleague of Kumar's said, "We have a problem of multiplicity." He meant that researchers must deal with multiple species of the parasite and multiple strains of each species, multiple parasite lifecycle stages, multiple strains of the mosquito, multiple epidemiologic areas, multiple im-mune responses, and so on. The parasite's complexity has ensured its survival for millennia and enshrined it as one of the most tenacious killers of human beings.

The drama begins in the belly of the female Anopheles.

* * *

When she takes her blood meal from a malarious person, she also sucks in male and female forms of the parasite (called gametocytes). As the blood arrives in the mosquito's midgut, the gametocytes sense the temperature and pH change and begin transforming almost instantly, as described in Bruce-Chwatt's Essential Malariology. The male gametocyte divides into four to eight smaller male cells called gametes. "This is quite a dramatic process. In less than 10 minutes, one parasite reproduces three times," says Kumar. Each female gametocyte matures into one female gamete. Similar to fertilization of a mammalian egg by the sperm, a male gamete presses itself into the female gamete and fertilizes it, forming a zygote. The gametes have only been in the mosquito midgut for 20 to 30 minutes.

Within 24 hours, the zygote transforms into a banana-like shape, pierces the mosquito's midgut wall, and forms a cyst on its outer surface. Inside the cyst, its nucleus divides repeatedly over a week-long period, forming a thousand or so spaghetti-like shapes called sporozoites, which eventually burst through the cyst wall and spread through the mosquito's body cavity. The sporozoites that reach the mosquito's salivary glands will survive, ready to infect a human host when the mosquito takes her next blood meal.

The malaria parasite has been infecting people for so long that one malaria expert argues that man's primate ancestors were "recognizably malarious before they were recognizably human." Indeed, humans have written about deadly fevers similar to malaria as long as they have been writing. More than 2,500 years ago, Hippocrates described the clinical nature of malaria and its complications. Throughout recorded history, the parasite has unleashed its power to conquer armies and humble civilizations. At times malaria has treated humanity more as a bug to crush than the other way around.

Before the age of scientific discovery, human imagination struggled to explain malaria's source, whether it be from a vengeful god or the mal'aria (bad air), as 17th-century Italians concluded. Fighting the disease, according to one modern newspaper account, was done with even greater imagination: eating a live spider on a butter pat; embracing a bald Brahmin widow at dawn; or resting the patient's head on the fourth book of the Iliad. Europeans only came upon a dependable treatment in the early 17th century, when Jesuit missionaries first learned about the fever-remedying properties of cinchona bark (whose active ingredient is quinine) from South American Indians.

However, separating the clinical source of the disease from millennia of superstition and ignorance really began less than 125 years ago at a French Army outpost in Algeria. On November 6, 1880, Charles Louis Alphonse Laveran placed blood from a malaria-infected patient on a microscope slide and observed malaria parasites for the first time. Within a few years, scientists around the world witnessed the parasites as well. (However, a doubtful William Osler, then at the University of Pennsylvania, reserved his acceptance of Laveran's discovery until 1887. Later, under Osler's direction, Johns Hopkins Hospital was the first in the world to do routine malaria blood smear examinations to diagnose febrile illness.)

That the malaria parasite existed in human blood was beyond doubt. But how could it move from one human to another? It wasn't until 1897 that a British Army doctor in India named Ronald Ross would positively link the malaria parasite to the mosquito. As malaria research developed, it was discovered that there was not one species of malaria parasite but four: Plasmodium falciparum (the deadly form), P. vivax (which causes almost half of all malaria cases), P. ovale, and P. malariae.

The same year Ross made his discovery, W. G. MacCallum (then a student at Hopkins' School of Medicine) first described sexual reproduction of the malaria parasite in the blood of a crow, greatly advancing knowledge of how the parasite reproduces. Soon after the School was founded in 1916, its faculty members and researchers began key work in malaria. Robert Hegner, who founded the medical zoology program at the School, continued MacCallum's research in avian malaria, studying host-parasite relationships and testing quinine derivatives. In the 1920s, Francis Root became a world-renowned expert on mosquito taxonomy. Public health experts mailed him specimens from all over the world for identifi-cation. Lloyd Rozeboom, ScD '34, another medical entomologist, continued mosquito research in order to assist control efforts.

Anopheles mosquitoes — the "brown mosquitoes" as Ross called them — were eventually linked with malaria. But they, like the parasite that rides within them, would prove to be a tricky, elusive target.

A School alumnus scored a major success in malaria control by targeting the mosquito. During the 1930s, 20,000 people in Brazil died in one of the worst malaria outbreaks in the Americas. The Brazilians turned to Fred Soper, DrPH '25, MPH '23, then a Rockefeller Foundation regional director. The blunt, intimidating Kansas native wielded absolute power in Brazil, deploying an army of 4,000 men who used diesel oil and Paris green (an arsenic-based concoction) to put down the epidemic in less than two years, as recounted in a July 2, 2001, New Yorker magazine article.

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