Putting the Bite On Malaria continued...
"You sleep under
a mosquito net. You close the windows. You spray the walls
Then you are praying that mosquitoes don't bite."
Taha Taha, Associate Professor
The advent of the insecticide DDT during World War II emboldened
Soper to help initiate in 1955 the Global Malaria Eradication Programme.
Initial results were encouraging, but as the years passed mosquitoes
became resistant to DDT, funding for the program dried up, and Rachel
Carson's 1962 publication of Silent Spring awakened people
to the toxic environmental effects of widespread use of chemicals
such as DDT. The Anopheles mosquito surged back, bringing
with it new malaria outbreaks. The program was abandoned in 1969.
(The current, more modest effort by the World Health Organization
— Roll Back Malaria — is trying to "halve the world's malaria
burden" by 2010.)
Current research at the School involves more subtle techniques
than spraying tons of chemicals on a given area in hopes of killing
From Nirbhay Kumar's perspective, a parasite of multiplicity calls
for multiple lines of attack. His research is attempting to stop
malaria transmission from three different angles. His most encouraging
results have come from the transmission-blocking vaccine he's been
working on since 1982. Rather than immunizing an individual against
the disease, Kumar's vaccine has the goal of preventing the individual
from transmitting the disease to others. "If we can contain
and stop transmission, then everything stops then and there,"
vaccine aims to stop development of sexual forms of the parasite
(male and female gametocytes) in the mosquito midgut. Kumar has
already demonstrated that the vaccine can produce enough antibodies
in mice to stop the parasite's sexual development. He is currently
testing the vaccine with rhesus monkeys. If that research is similarly
successful, a decision to pursue human trials can be made in two
to three years, says Kumar, who himself suffered a bout of malaria
as a PhD student in India in 1976.
Kumar and his colleagues have also shown that by removing a key
gene from the Plasmodium falciparum parasite they can suppress a
protein it needs for sexual development.
And a third research interest of Kumar's aims to stop the sporozoite
in its journey from the cyst on the mosquito's midgut to the salivary
glands. "No more sporozoites in the salivary gland, no more
transmission again," Kumar says.
again, the female mosquito searches for another blood meal. Imagine
she lands on you. The stylets of her proboscis saw into your skin.
She injects saliva into the wound to speed the process. Dozens of
Plasmodium sporozoites in her salivary glands spurt into
the tiny hole in your skin. A single sporozoite is enough to initiate
a full-blown infection.
If you live in an area where malaria
is endemic, a bite by an infected Anopheles
is nothing new. You are probably
permanently infected. For those who survive childhood, the constant
re-infection leads to a partial immunity. If you're otherwise healthy,
your immune system can hold off the parasite. But if you are weakened
by malnutrition or other infectious disease, malaria can suddenly
overwhelm you with debilitating illness or death. If the steady
re-infection stops for an extended time, for example if you move
to North America, you lose whatever immunity you had.
On the other hand, if you're not from a malarious area, you are
considered immunologically naïve. But it takes just one bite
of an infected Anopheles to
rid you of your naïveté.
It starts with the sporozoites carried in the mosquito's
saliva into the bite on your skin. Once in the bloodstream, a sporozoite
can reach the liver within minutes. There, it invades a liver cell
and stealthily starts reproducing. Your body, with its powerful
immune system, stands by dumbly. Symptomless, you walk about completely
unaware of the firestorm about to erupt in your body.
one of the 2 billion people of the world living in an area threatened
by malaria, Taha Taha, MD, PhD '92, MPH '86, associate professor in Epidemiology,
took regular precautions to stave off malaria infection when he
was working in Malawi in the mid-1990s. "You do the little
ritual things," says Taha, who grew up in Sudan and battled
malaria there as well. "You sleep under a mosquito net. You
close the windows, check to make sure the screens aren't damaged.
You spray the walls [regularly with insecticides]. Then you are
praying that mosquitoes don't bite."
At some level, the likelihood of getting malaria from an Anopheles
mosquito becomes a dance of numbers. There are more than 3,000 species
of mosquitoes. Of the 420 species of Anopheles, about 70
are capable of transmitting malaria. And of those 70, only about
30 to 40 are considered "good transmitters," according
to Douglas Norris, PhD, an assistant professor in MMI. "For
any one of those species, only 5 to 10 percent of the population
are capable of transmitting malaria," Norris says. These odds
seem favorable to humans until one factors in the countless numbers
of Anopheles mosquitoes that range over the globe.
While they may be found all over the world, Anopheles mosquitoes
naturally cause the greatest concern in malarious regions. Suzanne
Maman, PhD, an assistant scientist in International Health, has
worked in Kenya and Tanzania, where malaria is a daily fact of life.
"When somebody says, 'I have malaria,' it's not like everybody
is shocked," Maman says. "They just live with it. They
describe malaria like a flu.
having said that, it is the number one killer for children under
five and pregnant women," who may succumb to severe anemia,
cerebral malaria, or renal dysfunction, she says.
Clive Shiff, PhD, an associate professor in MMI and a veteran of
more than 30 years of malaria control in Africa, says he has found
that some Tanzanians suffered 300 to 1,000 infectious bites per
person per year one to three infections per day. Among schoolchildren
ages 12 and 13, some 60 percent were infected with malaria. "This
is debilitating. These kids couldn't concentrate on their work,"
he says. "But people survive. You see people doing work, and
women having children."
* * *
Inside your body, the killer is multiplying.
Within a week of its invasion, a single Plasmodium
parasite can multiply into tens of thousands of parasites. The frantic
reproductive pace is interrupted when the parasites (now called
merozoites) burst out of the liver cell. Each merozoite invades
the nearest red blood cell, where it feeds on the hemoglobin. One
merozoite will yield a dozen or more merozoites every 48 to 72 hours
(depending on the type of malaria). The cycle of reproduction, bursting
free, and invading new red blood cells continues over and over until
literally billions swarm in the blood.
|LAUNCHING THE JOHNS HOPKINS
MALARIA RESEARCH INSTITUTE
Since the euphoric days in May when the School announced
a $100 million gift to found the Johns Hopkins Malaria Research
Institute, celebration has given way to rounds of organizational
meetings, search committee meetings, and faculty recruitment
things off the ground," says Diane Griffin, MD, PhD,
chair of the W. Harry Feinstone Department of Molecular
Micro-biology and Immunology (MMI). With new projects getting
under way in the next few months, Griffin and others are
designing an infrastructure of people, facilities, and equipment
for the Institute.
Over the next five years,
10 to 12 new faculty members will be hired. They will have
appointments in MMI, Biochemistry and Molecular Biology,
Biostatistics, and International Health. Piles of CVs from
experts in entomology, structural biology, bioinformatics,
molecular biology, parasitology, immunology, and other areas
have already arrived.
Faculty interviews will
begin this fall. A minimum of 50 faculty, students, postdocs,
and support team members will eventually staff the Institute,
according to Griffin.
Space will be cramped
until 2004 when the Teaching and Research buildings (TR)
5 and 6 will be completed. Until then, some lab space will
open up early next year as some researchers move to TR3,
the latest addition to the School's main building. Despite
the space restrictions, the Institute has already begun
to acquire the necessary state-of-the-art equipment it needs.
The Institute recently purchased, in partnership with the
departments of Environmental Health Sciences and Biochemistry,
a $200,000 microarray facility used in analyzing changes
in gene expression.
at the School are already fanning out across the globe to
initiate collaborative research. Douglas Norris, PhD, assistant
professor in MMI, and Clive Shiff, PhD, associate professor
in MMI, spent part of their summer in Africa meeting with
colleagues there and working out the logistics of potential
collaborations. Additionally, malaria researchers from the
U.S. Navy and Army and the World Health Organization's Roll
Back Malaria program visited this summer.
Griffin, MMI professor
Nirbhay Kumar, and others are already preparing for the
Institute's first conference: a January 2002 meeting on
malaria in the post-genomic era.
Furthering the Institute's
"basic science" initiative, researchers will be
working to better understand the parasite, the disease-host
response, what makes the mosquito such a good transmitter
of malaria, and other issues. The ultimate goal is development
of a vaccine and new drugs.
David Sullivan, MD,
assistant professor in MMI, says he believes the basic science
acquired at the Institute will go beyond the specific results
of new drugs and vaccine candidates. "It's like the
space program. A lot of technology used to monitor astronauts
in space is now used to take care of patients here,"
he says. "A lot of research knowledge gained in tackling
malaria can be used in other research."
The merozoite invades the red blood cell primarily to dine on hemoglobin
to fuel its astounding reproductive capacity. Even in mild infections,
the merozoite consumption of hemoglobin can be debilitating, leaving
the infected person feeling exhausted, as if he or she has just
run a marathon or performed a couple days of hard labor, says MMI's
Sullivan researches the parasite's vulnerable iron metabolism in
the red blood cell. There, the parasite encounters a large amount
of what is known as "heme iron" in the hemoglobin. "Red
blood cells have 20,000 times the iron concentration of other mammalian
cells," says Sullivan. "The parasite has to detoxify the
iron through a unique crystallization process."
Ever adaptable, the parasite makes crystal polymers
of the heme iron, metabolizes the unwanted iron, and sequesters
it. Chloroquine, the powerful antimalarial drug that successfully
treated the disease for decades, inhibits the parasite's crystal-making
detoxification efforts. The parasite essentially overdoses on the
excess iron (which makes toxic oxygen radicals). However, the parasite
has acquired resistance in recent years to chloroquine in Africa,
Southeast Asia, and South America. Sullivan's hope is that a better
understanding of the parasite's iron metabolism will lead to more
Gary Posner, PhD, Scowe Professor of Chemistry at Homewood with
a joint appointment at the School, is also targeting the parasite's
iron metabolism. Using "molecular architecture," Posner,
Theresa Shapiro, MD, PhD, professor of Clinical Pharmacology in
the School of Medicine, and their students have created a synthetic
antimalarial. It is based on the artemisia plant, long used by the
Chinese as an herbal remedy for malaria. The drug interacts with
iron to generate oxygen and carbon radicals that destroy the parasite.
In late August, Posner announced that preclinical testing in mice
and rats had shown the carboxyphenyl trioxane compound to be safe
and effective. Human testing of the new antimalarial drug is still
two to five years away.
Other researchers at the National Institutes of Health and
in Britain are trying, like Posner and Sullivan, to stop the parasite's
merozoite stage in the blood. Meanwhile, the U.S. Navy and the Army
have projects under way to develop vaccines that target the sporozoites
in humans just after the mosquito bites.
Ultimately, even if scientists develop a vaccine that successfully
knocks out the parasite during one of its life stages, that may
not be enough. The vaccine would not only have to be 100 percent
effective, but would also have to stand up to Plasmodium's
expert ability to develop resistance through mutations. Explains
Kumar: "Given the complexity and smartness of the parasite,
I think that is expecting too much. In the end, we may have to make
a cocktail vaccine, a vaccine that targets the parasite at different
stages in the life cycle."
* * *
Too late, your body recognizes it has been
Depending on the species of Plasmodium
parasite, you may feel nothing for 9 to 30 days after the mosquito
bite. Symptoms usually begin with malaise and fatigue. You may become
dizzy and nauseated. You might think it is a cold or flu. Soon,
however, malaria is unmistakable. The horrors of the malaria rigor
(pronounced RYE-gor) begin. You start to shiver, mildly at first
and then violently. Your entire body shakes and your teeth chatter
uncontrollably. You grab for more blankets, desperate for warmth.
Finally, the warmth comes, but you keep getting warmer. Hot. Your
temperature increases. You kick off any covers. Your heart races.
For two to six hours, your skin burns. Then, you sweat profusely,
drenching the sheets. Your fever peaks at 106 degrees, before declining
slowly. The rigor lasts 8 to 12 hours. If your case of malaria follows
the classical model, you will suffer this every 48 or 72 hours,
a cycle that continues until drug therapy or your body's immune
response subdues the parasite. If, however, you are an infant or
pregnant woman infected with Plasmodium falciparum, you risk
* * *
Some researchers are bypassing the parasite altogether and focusing
on the other host in the malaria cycle: the Anopheles mosquito.
Norris, a vector biologist in MMI, studies the basic science of
mosquito populations in order to control them more effectively.
He tackles difficult questions: What genetically defines a mosquito
population? How big is a given population? Is its range the size
of a village or 60 kilometers square?
"We're applying really high-end molecular tools to field populations,"
Norris says. "We are at the point where we can do essentially
paternity testing on mosquitoes to find out how much transfer of
genetic material is going on."
"We are at the point
where we can do essentially paternity testing on mosquitoes
to find out how much transfer of genetic material is going
Douglas Norris, Assistant Professor
Conventional thinking had been that female mosquitoes mate once
in their lifetimes, store the male's sperm, and fertilize eggs as
they are deposited. Recent studies have shown, however, that female
mosquitoes can mate more than once, and on rare occasions with a
male outside of her population. "By doing the paternity test,
we can identify more than one mate's DNA," Norris says. "We
can sample the mom pretty easily we have the whole mosquito
and we can also sample the dad - from the [stored] sperm."
By studying mosquito populations and how genetic material passes
through them, researchers can better predict the likelihood of a
mosquito population acquiring insecticide resistance.
* * *
As the Plasmodium parasite grinds along in its seemingly
endless life cycle in mosquito and man, researchers are divining
knowledge from the parasite's multiplicities, seeking out its weak
points and learning where the odds favor a successful attack. The
scientists rely on multiplicities of their own, drawing on genetic,
social, biological, statistical, chemotherapeutic, and other knowledge
that will eventually enable them to extract the parasite from its
eternal reservoir, mankind.
"Basically, the parasite has developed a biological mechanism
that has allowed it to survive forever, as long as human beings
have existed," says Kumar. "We are talking about breaking
a symbiotic relationship between the parasite and host. It's not
going to be easy. But the fight is on."