The meandering Moei river marks the natural boundary between Thailand and Myanmar. Its muddy waters are at their fullest, but Francois Nosten
still crosses them in just a minute, aboard a narrow, wooden boat.
In the dry season, he could wade across. As he steps onto the western riverbank, in Myanmar, he passes no checkpoint and presents no passport.
In the dry season, he could wade across. As he steps onto the western riverbank, in Myanmar, he passes no checkpoint and presents no passport.
The air is cool. After
months of rain, the surrounding jungle pops with vivid lime and emerald
hues. Nosten climbs a set of wooden slats that wind away from the bank,
up a muddy slope. His pace, as ever, seems relaxed and out of kilter
with his almost permanently grave expression and urgent purpose.
Nosten,
a rangy Frenchman with tousled brown hair and glasses, is one of the
world's leading experts on malaria. He is here to avert a looming
disaster. At the top of the slope, he reaches a small village of simple
wooden buildings with tin and thatch roofs.
This is Hka Naw Tah, home to
around 400 people and a testing ground for Nosten's bold plan to
completely stamp out malaria from this critical corner of the world.
Malaria is the work of
the single-celled Plasmodium parasites, and Plasmodium falciparum chief
among them. They spread between people through the bites of mosquitoes,
invading first the liver, then the red blood cells. The first symptoms
are generic and flu-like: fever, headache, sweats and chills, vomiting.
At that point, the immune system usually curtails the infection. But if
the parasites spread to the kidneys, lungs and brain, things go downhill
quickly. Organs start failing. Infected red blood cells clog the
brain's blood vessels, depriving it of oxygen and leading to seizures,
unconsciousness and death.
When Nosten first arrived
in Southeast Asia almost 30 years ago, malaria was the biggest killer
in the region. Artemisinin changed everything. Spectacularly fast and
effective, the drug arrived on the scene in 1994, when options for
treating malaria were running out. Since then, "cases have just gone
down, down, down," says Nosten. "I've never seen so few in the rainy
season -- a few hundred this year compared to tens of thousands before."
But he has no time for
celebration. Artemisinin used to clear P. falciparum in a day; now, it
can take several. The parasite has started to become resistant. The
wonder drug is failing. It is the latest reprise of a decades-long
theme: we attack malaria with a new drug, it mounts an evolutionary
riposte.
Back in his office,
Nosten pulls up a map showing the current whereabouts of the resistant
parasites. Three colored bands highlight the borders between Cambodia
and Vietnam, Cambodia and Thailand, and Thailand and Myanmar (Burma).
Borders. Bold lines on maps, but invisible in reality. A river that can
be crossed in a rickety boat is no barrier to a parasite that rides in
the salivary glands of mosquitoes or the red blood cells of humans.
History tells us what
happens next.
Over the last century, almost every frontline antimalarial
drug -- chloroquine, sulfadoxine, pyrimethamine -- has become obsolete
because of defiant parasites that emerged from western Cambodia. From
this cradle of resistance, the parasites gradually spread west to
Africa, causing the deaths of millions. Malaria already kills around 660,000 people every year, and most of them are African kids.
If artemisinin resistance
reached that continent, it would be catastrophic, especially since
there are no good replacement drugs on the immediate horizon.
If you want to eliminate artemisinin resistance, you have to eliminate malaria.
Francois Nosten, Professor in Tropical Medicine
Francois Nosten, Professor in Tropical Medicine
Nosten thinks that
without radical measures, resistance will spread to India and
Bangladesh. Once that happens, it will be too late.
Those countries are
too big, too populous, too uneven in their health services to even dream
about containing the resistant parasites. Once there, they will
inevitably spread further. He thinks it will happen in three years,
maybe four.
"Look at the speed of change on this border. It's
exponential. It's not going to take 10 or 15 years to reach Bangladesh.
It'll take just a few. We have to do something before it's too late."
Hundreds of scientists
are developing innovative new ways of dealing with malaria, from
potential vaccines to new drugs, genetically modified mosquitoes to
lethal fungi. As Nosten sees it, none of these will be ready in time.
The only way of stopping artemisinin resistance, he says, is to
completely remove malaria from its cradle of resistance. "If you want to
eliminate artemisinin resistance, you have to eliminate malaria," says
Nosten. Not control it, not contain it. Eliminate it.
That makes the Moei
river more than a border between nations. It's Stalingrad. It's
Thermopylae. It's the last chance for halting the creeping obsolescence
of our best remaining drug. What happens here will decide the fate of
millions.
Eradicating malaria
The world tried to
eliminate malaria 60 years ago. Malaria was a global affliction back
then, infecting hundreds of thousands of troops during World War II.
This helped motivate a swell of postwar research.
To fight the disease,
in 1946 the USA created what is now the Centers for Disease Control and Prevention (CDC), the country's premier public health institute. After a decisive national eradication program, the nation became malaria-free in 1951. Brazil had also controlled a burgeoning malaria epidemic with insecticides.
Meanwhile, new weapons
had emerged. The long-lasting insecticide DDT was already being widely
used and killed mosquitoes easily.
A new drug called chloroquine did the
same to Plasmodium. Armed with these tools and buoyed by earlier
successes, the World Health Organization formally launched the Global
Malaria Eradication Program in 1955. DDT was sprayed in countless homes.
Chloroquine was even added to table salt in some countries. It was as
ambitious a public health initiative as has ever been attempted.
It worked to a point.
Malaria fell dramatically in Taiwan, Sri Lanka, India, the Caribbean,
the Balkans, and parts of the south Pacific.
But ultimately the problem
was too big, the plan too ambitious. It barely made a dent in
sub-Saharan Africa, where public health infrastructure was poor and
malaria was most prevalent.
And its twin pillars soon crumbled as P.
falciparum evolved resistance to chloroquine and mosquitoes evolved
resistance to DDT. The disease bounced back across much of Asia and the
western Pacific.
Despite several successes, its overall failure had a chilling impact on
malaria research. Investments from richer (and now unaffected)
countries dwindled, save for a spike of interest during the Vietnam War.
The best minds in the field left for fresher challenges. Malaria, now a
tropical disease of poor people, became unfashionable.
'If you want to travel, be a doctor'
Francois Nosten always
wanted to travel. His father, a sailor on merchant ships, returned home
with stories of far-flung adventures and instilled a deep wanderlust.
Nosten's original plan was to work on overseas development projects, but
one of his teachers pushed him down a different path. "He said the best
thing you can do if you want to travel anywhere is to be a doctor.
That's why I started medical school." As soon as he graduated, he joined
Médecins Sans Frontières and started living the dream. He flew off to
Africa and Southeast Asia, before arriving in Thailand in 1983. There,
he started treating refugees from Myanmar in camps along the Thai
border.
In 1985, an English
visitor arrived at the camps and Nosten took him for a random tourist
until he started asking insightful questions about malaria. That man was
Nick White.
A British clinician, he was drawn to Bangkok in 1980 by the
allure of the tropics and a perverse desire to study something
unfashionable. The University of Oxford had just set up a new tropical
medicine research unit in collaboration with Bangkok's Mahidol
University, and White was the third to join.
"The rosbif and the
frog", as Nosten puts it, bonded over an interest in malaria, a desire
to knuckle down and get things done, and a similar grouchy conviviality.
They formed a close friendship and started working together.
In 1986, they set up a
field station for White's Bangkok research unit: little more than a
centrifuge and microscope within Nosten's rickety house. Three years
later, Nosten moved to Shoklo, the largest refugee camp along the
Thai--Myanmar border and home to around 9,000 people.
Most were Karen --
the third largest of Myanmar's 130 or so ethnic groups -- who were fleeing persecution from the majority Bamar government. Nosten worked out of a bamboo hospital -- the first Shoklo Malaria Research Unit.
We once had to hide in a hole for the night, with bullets flying around.
Francois Nosten, Professor in Tropical Medicine
Francois Nosten, Professor in Tropical Medicine
Malaria was rife. Floods
were regular. Military leaders from both Thailand and Myanmar
occasionally ordered Nosten to leave. Without any electricity, he often
had to use a mirror to angle sunlight into his microscope. He loved it.
"I'm not a city person," he says. "I couldn't survive in Bangkok very
well. I wasn't alone in Shoklo but it was sufficiently remote."
The
immediacy of the job and the lack of bureaucracy also appealed. He could
try out new treatments and see their impact right away. He trained
local people to detect Plasmodium under a microscope and help with
research.
He even met his future wife -- a Karen teacher named Colley
Paw, who is now one of his right-hand researchers (White was the best
man at their wedding). These were the best years of his life.
The Shoklo years ended
in 1995 after a splinter faction of Karen started regularly attacking
the camps, in a bid to force the refugees back into Myanmar. "They came
in and started shooting," says Nosten. "We once had to hide in a hole
for the night, with bullets flying around."
The Thai military, unable to
defend the scattered camps, consolidated them into a single site called
Mae La -- a dense lattice of thatch-roofed houses built on stilts,
which now contains almost 50,000 people. Nosten went with them.
He has since expanded
the Shoklo Unit into a huge hand that stretches across the region. Its
palm is a central laboratory in the town of Mae Sot, where Nosten lives,
and the fingers are clinics situated in border settlements, each with
trained personnel and sophisticated facilities.
The one in Mae La has a
$250,000 neonatal care machine, and can cope with everything short of
major surgery. Nosten has also set up small "malaria posts" along the
border. These are typically just volunteer farmers with a box of
diagnostic tests and medicine in their house.
"I don't know anybody
else who could have done what Francois has done," says White. "He'll
underplay the difficulties but between the physical dangers, politics,
logistical nightmares, and the fraught conditions of the refugees, it's
not been easy. He's not a shrinking violet."
Thanks to Nosten's
network, locals know where to go if they feel unwell, and they are never
far from treatments. That is vital. If infected people are treated
within 48 hours of their first symptoms, their parasites die before they
get a chance to enter another mosquito and the cycle of malaria breaks.
"You deploy early identification and treatment, and malaria goes away,"
says Nosten. "Everywhere we've done this, it's worked."
Wonder drug
Victories in malaria are
often short-lived. When Nosten and White teamed up in the 1980s, their
first success was showing that a new drug called mefloquine was
excellent at curing malaria, and at preventing it in pregnant women.
Most drugs had fallen to resistant parasites and the last effective one
-- quinine -- involved a week of nasty side-effects. Mefloquine was a
godsend.
We saw more and more treatment failures, patients coming back weeks later with the same malaria.
Francois Nosten, Professor in Tropical Medicine
Francois Nosten, Professor in Tropical Medicine
But within five years,
P. falciparum had started to resist it too. "We tried different things
like increasing the dose, but we were clearly losing the drug," says
Nosten. "We saw more and more treatment failures, patients coming back
weeks later with the same malaria. We were really worried that we
wouldn't have any more options."
Salvation came from
China. In 1967, Chairman Mao Zedong launched a covert military
initiative to discover new antimalarial drugs, partly to help his North
Vietnamese allies, who were losing troops to the disease. It was called Project 523.
A team of some 600 scientists scoured 200 herbs used in traditional
Chinese medicine for possible antimalarial chemicals.
They found a clear
winner in 1971 -- a common herb called qing hao (Artemisia annua or
sweet wormwood). Using hints from a 2,000-year-old recipe for treating
hemorrhoids, they isolated the herb's active ingredient, characterized
it, tested it in humans and animals, and created synthetic versions.
"This was in the aftermath of the Cultural Revolution," says White.
"Society had been ripped apart, there was still a lot of oppression, and
facilities were poor. But they did some extremely good chemistry."
Sweet wormwood gave rise to the anti-malrial drug Artemisinin.
The results were
miraculous. The new drug annihilated even severe forms of
chloroquine-resistant malaria, and did so with unparalleled speed and no
side-effects. The team named it Qinghaosu. The West would know it as
artemisinin. Or, at least, they would when they found out about it.
Project 523 was shrouded
in secrecy, and few results were published. Qinghaosu was already being
widely used in China and Vietnam when the first English description
appeared in the Chinese Medical Journal in 1979.
Western scientists,
suspicious about Chinese journals and traditional medicine, greeted it
with skepticism and wasted time trying to develop their own less
effective versions. The Chinese, meanwhile, were reluctant to share
their new drug with Cold War enemies.
During this political
stalemate, White saw a tattered copy of the 1979 paper. He travelled to
China in 1981, and returned with a vial of the drug, which he still
keeps in a drawer in his office. He and Nosten began studying it,
working out the right doses, and testing the various derivatives.
They realized that
artemisinin's only shortcoming was a lack of stamina.
People clear it so
quickly from their bodies that they need seven daily doses to
completely cure themselves. Few complete the full course. White's
ingenious solution was to pair the new drug with mefloquine -- a
slower-acting but longer-lasting partner.
Artemisinin would land a
brutal shock-and-awe strike that destroyed the majority of parasites,
mefloquine would mop up the survivors.
If any parasites resisted the
artemisinin assault, mefloquine would finish them off. Plasmodium would
need to resist both drugs to survive the double whammy, and White deemed
that unlikely.
Just three days of this artemisinin combination therapy
(ACT) was enough to treat virtually every case of malaria. In theory,
ACTs should have been resistance-proof.
Nosten started using
them along the Thai--Myanmar border in 1994 and immediately saw results.
Quinine took days to clear the parasites and left people bed-ridden for
a week with dizzy spells. ACTs had them returning to work after 24
hours.
Rapid parasite clearance is the hallmark of artemisinins. That property suddenly disappeared.
Arjen Dondorp, deputy director, Mahidol-Oxford Tropical Medicine Research Unit in Bangkok
Arjen Dondorp, deputy director, Mahidol-Oxford Tropical Medicine Research Unit in Bangkok
But victories in malaria
are often short-lived.
In the early 2000s, the team started hearing
rumours from western Cambodia that ACTs were becoming less effective.
White tried to stay calm. He had heard plenty of false alarms about
incurable Cambodian patients, but it always turned out that they were
taking counterfeit drugs. "I was just hoping it was another of those,"
he says.
It was not. In 2006,
Harald Noedl from the Medical University of Vienna started checking out
the rumors for himself.
In the Cambodian village of Ta Sanh, he treated
60 malaria patients with artesunate (an artemisinin derivative) and
found that two of them carried exceptionally stubborn parasites. These
infections cleared in four to six days, rather than the usual two.
And
even though the patients stayed in a clinic outside any malaria
hotspots, their parasites returned a few weeks later.
"I first presented those
data in November 2007 and as expected, people were very skeptical,"
says Noedl. After all, a pair of patients is an epidemiological blip.
Still, this was worrying enough to prompt White's team to run their own
study in another nearby village.
They got even worse news. The 40 people
they treated with artesunate took an average of 3.5 days to clear their
parasites, and six of them suffered from rebounding infections within a
month. "Rapid parasite clearance is the hallmark of artemisinins," says
Arjen Dondorp, one of White's colleagues based in Bangkok. "That
property suddenly disappeared."
Despite the hopes that
ACTs would forestall artemisinin's expiry, resistance had arrived, just
as it had done for other antimalarials. And, as if to rub salt in the
wound, it had come from the same damn place.
SOURCE: http://edition.cnn.com
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