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
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
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,
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.
Separating the clinical
source of malaria from millennia of superstition and ignorance
began 120 years ago at a French army outpost in Algeria.
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
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,
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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