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To Beat Malaria, We Need to See It as an Ecological Problem

It’s easy to just think of malaria as a medical problem. It is caused by single-celled parasites—Plasmodium—that are spread through the bites of other parasites—mosquitoes. To beat the disease, we need to neutralise either Plasmodium or its mosquito carriers, using drugs, insecticides, nets, or even genetically-modified competitors.

But malaria is also an ecological problem. Mosquitoes aren’t static, unchanging targets. They move around. They mate. They breed in some areas and not in others. Their populations swell and contract throughout the year. They bite at varying times of day. We need to understand these subtle quirks of mosquito life, because they all have a huge impact on our strategies for fighting malaria.

Consider the Sahel—a belt of land that stretches across Africa’s waist, with the Sahara to the north and savannahs to the south. In this region, half a million people die from malaria every year—which is puzzling. Every year, between December and June, the Sahel goes through an intense dry season. Rain hardly falls. Stagnant pools and puddles, in which mosquitoes lay their eggs, evaporate. The adults ought to die before they can start a new generation. And yet, when the rains return, so do malarial mosquitoes, in huge numbers. How do they survive?

Scientists have puzzled over this ‘dry season paradox’ for more than a century. Some said that the insects persist through the dry spell in a dormant state, while others felt that they migrate over long distances to more habitable climes.

Now, a team of scientists led by Adama Dao from the University of Sciences in Mali, and Tovi Lehmann from the US National Institutes of Health, have finally found that both answers are right. Some species of malarial mosquitoes persist; others travel. And that has big implications for our attempts to stop malaria in this critical region.

The same pond near Thierola village, during the wet and dry seasons. Credit: Drs. Adama Dao, Alpha S. Yaro and Tovi Lehmann
The same pond near Thierola village, during the wet and dry seasons. Credit: Drs. Adama Dao, Alpha S. Yaro and Tovi Lehmann

Under Dao’s leadership, a team of researchers from Mali spent years counting the numbers of malarial mosquitoes in the Malian village of Thierola. They checked for larvae in every puddle, tree hole, or well they could find. They collected adults from every house in the village, and used a variety of traps to capture those flying outside. And they did this on every fourth day or so, for five years.

“How mosquitoes survive the dry season is a deceptively simple question, but it has been very difficult to answer,” says Jason Rasgon from Pennsylvania State University . “It takes the kind of heroic sampling effort that the authors performed to get a handle on this issue.”

The team found different patterns for each of the three different species of malarial mosquitoes in the area. Anopheles coluzzi is the most common of these. Its populations peak in September and October, at the height of the wet season, before plummeting in November as the larval sites dry up. They stay at low levels for most of the dry months, with two exceptions: huge short-lived population spikes in December and April, when numbers suddenly soar by 10 to 90 times. And once it starts properly raining in June, A.coluzzi bounces back almost immediately.

These patterns suggest that the adults somehow wait out the dry season in a dormant state. They can take advantage of any rare bursts of rain, and they’re ready and waiting when the wet season truly begins.

The other two species—Anopheles gambiae and Anopheles arabiensis—showed very different patterns. Neither of them had any peaks during the dry season. Once their populations fell, they stayed that way until the rains returned. Even then, it took a few months for them to bounce back. It seems that these two species survive by migrating to other areas, hundreds of kilometres away.

Credit: Dao et al, 2014. Nature.
Credit: Dao et al, 2014. Nature.

“Any mosquito paper that tries to unravel their complex ecology is a winner in my eyes,” says James Logan from the London School of Hygiene and Tropical Medicine. “There is much about malaria mosquito ecology and biology that we still don’t understand, so studies like this could have large implications in the control of diseases like malaria.”

For example, the team suspects that A.coluzzi’s ability to survive in a dormant state allows it to maintain cycles of malaria transmission that would otherwise break during the dry season. By peaking twice during the drought, it can continuously shuttle Plasmodium between humans at a time when the parasite should face dead-ends. When the wet season begins, A.coluzzi can immediately start ratcheting up these cycles of transmission. And when A.gambiae and A.arabiensis return in September and October, they kick things into even higher gear.

Lehmann’s team are now trying to break these cycles by finding A.coluzzi’s dry-season hide-outs and blitzing them with insecticides. They are testing this approach in a larger number of villages.

It seems counter-intuitive to go after the mosquitoes when they’re at their rarest, but those rare populations are critical—they are the seeds of the next wet season’s boom. “By hitting the late dry-season peak and the early wet-season surge, we think we’ll virtually eliminate the seed population,” says Lehmann. “We think we could potentially cut down transmission in those areas by 75 percent or more, and it would be very cost-effective.”

His results also have implications for other malaria control strategies. For example, some scientists are trying to develop genetically modified mosquitoes that cannot harbour Plasmodium, and that would outcompete local insects. But if these GM-mozzies cannot last through the dry season, their impact would be short-lived. And if A.gambiae and A.arabiensis return in the wet season, flying in from distant parts of the Sahel, they would reintroduce a fresh pot of parasites every year. “The long-term planning of the battle against malaria cannot ignore these phenomena,” says Lehmann.

Unfortunately, that’s exactly what people tend to do. Many historical attempts to control mosquitoes have failed dismally because they were build on shoddy ecological foundations. As Heather Ferguson from the University of Glasgow once wrote: “A lot of the knowledge gaps that hindered previous attempts still remain… We have made substantially more headway in understanding the reproductive biology of species with no direct public health or economic importance, such as Drosophila, fur seals and blue tits, than we have done for this vector that kills millions.”

I wrote about this in a piece for Slate in 2011:

“Crucial ecological research on mosquitoes is trapped in a financial no-man’s land. Organizations that fund basic research into issues like how insects behave assume that biomedical agencies will foot the bill, while these agencies are more likely to prioritize research with more obvious and immediate clinical impact. But the necessary ecological studies would not be expensive. Ferguson estimates that it would take just $500,000 to fund 10 students in the field, an act that “could easily quadruple our knowledge of this area within a few years.”

For example, in 2008, her student Kija Mg’Habi worked in an isolated, malarious part of Tanzania and discovered that among Anopheles gambiae (a species that carries malaria), the medium-sized males get the most sex. You might expect the biggest males to outcompete their smaller rivals, but they were actually six times less successful. This is exactly the type of information you need if you want your modified mosquitoes to outcompete their natural brethren… It may not be as sexy as modifying genes, but ecology is tantamount to knowing your enemy, and that surely is a cornerstone of victory.”

Reference: Dao, Yaro, Diallo, Timbine, Huestis, Kassogue, Traore, Sanogo, Samake & Lehmann. 2014. Signatures of aestivation and migration in Sahelian malaria mosquito populations. Nature http://dx.doi.org/10.1038/nature13987

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The Worst Bit About Feeding Mosquitoes Is The Waiting

The worst thing about feeding hundreds of mosquitoes on your own blood is not the itching – if you do it enough times, your body gets used to the bites. It’s not even the pain, although it is always painful since the mosquitoes will use their snouts to root about your flesh in search of a blood vessel.

It is more that, sometimes, the little suckers take their time.

“They just walk around on your arm. You’re sitting there and thinking, ‘Seriously? I have things to do’,” says Chiara Andolina.

Andolina is an infectious-disease researcher who works at the Shoklo Malaria Research Unit, a world-renowned laboratory nestled in an unassuming town near Thai–Myanmar border. She runs the Unit’s insectory, where mosquitoes are bred, reared, infected with the Plasmodium parasites that cause malaria, and dissected.

There are only five or six such facilities in Thailand, largely because the malarial mosquitoes of South-east Asia are delicate, wilting flowers. In Africa, malaria is transmitted by Anopheles gambiae – a hardy insect with catholic tastes. They will go without food for days. They will endure through tough environmental conditions. They will suck blood from rabbits, cows… basically anything that they can get their proboscis into.

Their Asian cousins, Anopheles dirus, are very different. “You blow on them a little bit and they’re like: ‘No. I’m not mating today. I’m upset.’” They also refuse to eat anything except human blood, which is why Andolina has to feed them herself.

She does this simply by sticking her arm through a muslin sock and into their cages. It takes half an hour and she does it every four days. “They’re very spoiled,” she says.

Andolina fed around 600 mosquitoes yesterday and you wouldn’t be able to tell – her arm is free of any marks because she has built up resistance to the allergens in the mosquito saliva. Her boss, François Nosten, had to fill in for her two weeks ago and his arm is still covered in welts. This is why there is no feeding rota. It’s just Andolina. She has tried to convince her research assistants to help but, for some strange reason, they aren’t keen.

The boxes contain two closely related species of mosquito: Anopheles dirus B and C. The two colonies have to be kept apart. If someone mixes them by mistake, it would be nigh impossible to fix the error. B and C look identical, even under the microscope, and only their genes reveal them to be distinct species. They also transmit very different malarial parasites: B carries Plasmodium falciparum, the main cause of malaria in these parts, while C transmits P. vivax. Andolina once spent a few years on an experiment that just wouldn’t work, because she was trying to infect one of the species with the wrong parasite.

Only female mosquitoes drink blood, and they use proteins in their meals to make the shells of their eggs. But they also need mating partners, and A. dirus are as finicky about sex as they are about food. Andolina used to have to force-mate them.

To begin: decapitate a male, and anaesthetise a female with ether. Next, unite the two by inserting the male’s still-protruding genitals into his unconscious partner. Get it right and the two insects (or one-and-a-half insects) lock together, sperm is transferred, and the female becomes pregnant. Andolina first learned to do this without a microscope. It took steady hands.

The females lay their eggs as little floating rafts. It takes two days for these to hatch into larvae, which hang from the water’s surface, breathing from their rear ends and sweeping up passing debris with brush-like mouthparts. Andolina keeps them in a succession of trays, nourished with tropical fish food. She needs to change the water regularly, or the larvae quickly succumb to all manner of bacterial, viral and fungal infections. They are not the toughest of species.

It takes another two weeks for them to turn into adults. Now, they’re ready for experiments. Typically, this involves infecting them with malaria.

Andolina loads a feeding pump with blood samples from people with malaria. The pump delivers the blood into a grey cylinder, with a membrane stretched across it. She places this on top of a sheet of muslin, draped over an empty noodle cup containing dozens of mosquitoes. The cylinder is like an upside-down feeding trough. The mosquitoes dangle upside-down from the muslin, pierce the adjacent membrane, and suck up the blood.

"Guys, what did you do with my noodlOH MY GOD!"
“Guys, what did you do with my noodlOH MY GOD!”

Once they are infected, security is paramount. The law dictates that there must be four doors between them and the outside world, so they’re kept inside an incubator within one of three adjoining rooms. Andolina counts them every day to make sure that none have escaped. If she ever misses one – and that hasn’t happened yet – she won’t be allowed to leave the lab until she has found and killed it.

“I don’t do it because I love mosquitoes,” says Andolina. Her work creates a ready supply of parasites. She provides these to collaborators in Paris and Singapore, who are trying to develop new drugs that target malarial parasites holding out in a patient’s liver.

More directly, she wants to see if a drug called primaquine can help to break the cycle of malaria transmission. The drug kills malarial parasites in the liver, but there’s a chance that it could also stop the mosquitoes from becoming infected. Andolina wants to see if mosquitoes are less likely to pick up the parasites after feeding on the blood of patients who have taken low doses of primaquine.

At high doses, the drug produces nasty side-effects in some patients. If lower doses are still effective, then primaquine could feature in the Shoklo Unit’s radical campaign to completely eliminate malaria from South-east Asia, by treating as many people as possible with antimalarial drugs.

This post first appeared on Mosaic as part of my feature on drug-resistant malaria.

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Can We Beat Drug-Resistant Malaria At Its Birthplace?

In the war against malaria, one small corner of the globe has repeatedly turned the tide, rendering our best weapons moot and medicine on the brink of defeat. I travelled to Thailand and Burma to meet the scientists who are trying to eliminate resistant malaria before it defeats our best remaining drug. This story originally appeared in Mosaic and is republished under a CC-BY 4.0 licence.  

The meandering Moei river marks the natural boundary between Thailand and Myanmar. Its muddy waters are at their fullest, but François 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.

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 South-east 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 coloured 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.

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.

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 programme, 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 Programme 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.

In 1969, the eradication programme was finally abandoned. 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.



François 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 South-east 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.

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 François 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.”


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.

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 haemorrhoids, they isolated the herb’s active ingredient, characterised 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.”

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 scepticism 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 realised 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.

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 rumours 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 sceptical,” 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.


Why has a small corner of western Cambodia, no bigger than Wales or New Jersey, repeatedly given rise to drug-beating parasites?

White thinks that the most likely explanation is the region’s unregulated use of antimalarial drugs. China supplied artemisinin to the tyrannical Khmer Rouge in the late 1970s, giving Cambodians access to it almost two decades before White conceived of ACTs. Few used it correctly. Some got ineffective doses from counterfeit pills. Others took a couple of tablets and stopped once their fever disappeared. P. falciparum was regularly exposed to artemisinin without being completely wiped out, and the most resistant parasites survived to spread to new hosts. There is a saying among malariologists: “The last man standing is the most resistant.”

Genetic studies hint at other explanations. Early last year, Dominic Kwiatkowski from the University of Oxford showed that some P. falciparum strains from west Cambodia have mutations in genes that repair faults in their DNA, much like some cancer cells or antibiotic-resistant bacteria. In other words, they have mutations that make them prone to mutating. This might also explain why, in lab experiments, they develop drug resistance more quickly than strains from other parts of the world. Evolution is malaria’s greatest weapon, and these ‘hypermutators’ evolve in fifth gear.

Kwiatkowski’s team also found that P. falciparum is spookily diverse in west Cambodia. It is home to three artemisinin-resistant populations that are genetically distinct, despite living in the same small area. That is bizarre. Without obvious barriers between them, the strains ought to regularly mate and share their genes. Instead, they seem to shun each other’s company. They are so inbred that they consist almost entirely of clones.

Kwiatkowski suspects that these parasites descended from some lucky genetic lottery winners that accumulated the right sets of mutations for evading artemisinin. When they mate with other strains, their winning tickets break up and their offspring are wiped out by the drug. Only their inbred progeny, which keep the right combinations, survive and spread.

It undoubtedly helps that South-east Asia does not have much malaria. In West Africa, where transmission is high, a child might be infected with three to five P. falciparum strains at any time, giving them many opportunities to mate and shuffle their genes. A Cambodian child, however, usually sees one strain at a time, and is a poor hook-up spot for P. falciparum. The region’s infrastructure may also have helped to enforce the parasites’ isolation: local roads are poor, and people’s movements were long constrained by the Khmer Rouge.

West Cambodia, then, could be rife with P. falciparum strains that are especially prone to evolving resistance, that get many opportunities to do so because antimalarial drugs are abused, and that easily hold on to their drug-beating mutations once they get them.

These are plausible ideas, but hard to verify since we still know very little about how exactly the parasites resist a drug. Earlier cases of resistance were largely due to mutations in single genes – trump cards that immediately made for invincible parasites. A small tweak in the crt gene, and P. falciparum can suddenly pump chloroquine out of its cells. A few tweaks to dhps and dhfr, the genes targeted by sulfadoxine and pyrimethamine, and the drug can no longer stick to its targets.

Artemisinin seems to be a trickier enemy. Curiously, P. falciparum takes a long time to evolve resistance to artemisinin in lab experiments, much longer than in the wild. Those strains that do tend to be weak and unstable. “I suspect you need a complicated series of genetic changes to make a parasite that’s not lethally unfit in the presence of these drugs,” says White. “It would be unusual if this was a single mutation.”

Practices such as unregulated drug use and misuse may help encourage and accelerate the rate of such changes out in the field. Kwiatkowski’s study suggests that the parasites may have evolved artemisinin resistance several times over, perhaps through a different route each time. Several groups are racing to find the responsible mutations, with news of the first few breaking in December 2013. That’s the key to quickly identifying resistant parasites and treating patients more efficiently. (Currently, you can only tell if someone has artemisinin-resistant malaria by treating them and seeing how long they take to get better.) “We want to be able to track resistance using blood spots on filter paper,” says Chris Plowe at the University of Maryland School of Medicine, whose group is one of those in the race.

But time is running out. From its origins in Cambodia, resistance has reached the Thai–Myanmar border. Nosten has shown that the proportion of patients who are still infected after three days of ACT has increased from zero in 2000 to 28 per cent in 2011. Most are still being cured, but as artemisinin becomes less effective, its partner drug will have to mop up more surviving parasites. Plasmodium will evolve resistance to the partner more quickly, driving both drugs towards uselessness.

This is already happening in western Cambodia, where ACTs are failing up to a quarter of the time and many people are still infected a month later. Long-lasting infections will provide parasites with more chances to jump into mosquitoes, and then into healthy humans. Malaria cases will rise. Deaths will follow. “This is the silence before the storm,” says Arjen Dondorp. “The threat is still slightly abstract and there’s still not that much malaria, which doesn’t help with a sense of urgency. If we suddenly see malaria exploding, then it’ll be a clear emergency, but it’ll also be too late.”


In his office at Mahidol University, Nick White is surrounded by yellowing monographs of old malaria research and overlooked by a wall-mounted mosaic of drug packets made by his daughter. He is now the chairman of the Mahidol–Oxford Tropical Medicine Research Unit and a mentor to the dozens of researchers within. He is gently ranting.

“Everything to do with change in malaria meets with huge resistance,” he says. He means political resistance, not the drug kind. He means the decade it took for the international community to endorse ACTs despite the evidence that they worked. He means the “treacle of bureaucracy” that he and Nosten swim through in their push to eliminate malaria.

“The global response to artemisinin resistance has been a bit pathetic. Everyone will tell you how important it is and there have been any number of bloody meetings. But there is little appetite for radical change.” He misses the old days when “you could drive a Land Rover across borders in your khaki shorts and spray things and do stuff”.

From the outside, things look rosier. Malaria is fashionable again, and international funding has gone up by 15 times in the last decade. Big organisations seem to be rallying behind the banner of elimination. In April 2013, the World Health Organization published a strategy called The Emergency Response to Artemisinin Resistance

“It’s a marvellous plan,” he says drily. “It says all the right things, but we haven’t done anything.” It follows two other strategies that were published in 2011 and 2012, neither of which slowed the spread of artemisinin resistance. Elimination became a dirty word after the noisy failures of the 1950s and 60s, and the new strategies look like the same old tactics for controlling malaria, presented under the guise of eradicating it. “They’re prescriptions for inertia,” says White.

Worse, they are channelling funds into ineffective measures. Take insecticide-treated bednets, a mainstay of malaria control. “We’ve had meetings with WHO consultants who said, ‘We don’t want to hear a word against bednets. They always work.’ But how cost-effective are they, and what’s the evidence they work in this region? The mosquitoes here bite early in the evening. And who’s getting malaria? Young men. Are they all tucked up in their bednets by 6 o’clock? No. They’re in the fields and forests. Come on! It’s obvious.”

He says that resources could be better devoted to getting rid of fake drugs and monotherapies where artemisinin is not paired with a partner. That would preserve ACTs for as long as possible. The world also needs better surveillance for resistant parasites. White is helping with that by chairing the World-Wide Anti-Malarial Resistance Network – a global community of scientists who are rapidly collecting data on how quickly patients respond to drugs, the presence of resistance genes, the numbers of fake drugs, and more.

White also wants to know if artemisinin-resistant parasites from South-east Asia can spread in African mosquitoes. Hundreds of mosquito species can transmit malaria, but P. falciparum is picky about its hosts. If resistant strains need time to adapt to new carriers, they might be slow to spread westwards. If they can immediately jump into far-off species, they are a plane ride away from Africa. “That changes your containment strategy,” says White, “but stupidly, it’s cut out of every research application we’ve ever made.”

He is pessimistic. “I’m pretty confident we won’t win but I think we should try a lot harder than we have been. If we didn’t pull out all the stops and kids start dying of artemisinin-resistant malaria, and we can trace the genetic origins of those parasites to South-east Asia, we shouldn’t sleep easy in our beds.”


The Mosquito breederWhen Nosten’s team first arrived at Hka Naw Tah in February, they slept and worked from the village’s unassuming temple. Using development funds from their grant, they put up a water tower and supplied electricity for the local school. In return, the villagers built them a clinic – a spacious, open-sided hut with a sloping tin roof, benches sitting on a dirt floor, a couple of tables holding boxes of drugs and diagnostic kits, treatment rooms, and a computer station. It took just two days to erect.

The Karen respect strong leadership but there is an easy-going camaraderie in the clinic. When we arrive, one of the research assistants is napping across a bench. Nosten walks over and sits on him. “You see, and I think this is a good sign, that it’s hard to tell who’s the boss and who’s the patient,” he says.

Most of the villagers don’t seem sick, but many of them have malaria nonetheless. Until recently, Nosten’s team had always searched for the parasites by examining a drop of blood under a microscope. If someone is sick, you can see and count the Plasmodium in their red blood cells. But in 2010, they started collecting millilitres of blood – a thousand times more than the usual drops – and searching for Plasmodium’s DNA. Suddenly, the proportion of infected people shot up from 10–20 per cent to 60–80 per cent. There are three, four, maybe six times as many infected people as he thought.

“We didn’t believe it at first,” says Nosten, “but we confirmed it and re-confirmed it.” Perhaps the tests were giving false positives, or picking up floating DNA from dead parasites? No such luck – when the team treated people with ACTs, the hidden parasites disappeared. They were real.

These ‘sub-microscopic infections’ completely change the game for elimination. Treating the sick is no longer good enough because the disease could bounce back from the hordes of symptomless carriers. The strike will have to be swift and decisive. If it’s half-hearted, the most resistant parasites will survive and start afresh. In malarial zones, you need to treat almost everyone, clearing the parasites they didn’t even know they had. This is Nosten’s goal in the border villages like Hka Naw Tah. He has support from the Bill and Melinda Gates Foundation, one of the few large funders to have truly grasped the urgency of the situation and who are “very much in the mood for elimination”.

Killing the parasites is easy: it just involves three days of ACTs. Getting healthy people to turn up to a clinic and take their medicine is much harder. The team have spent months on engagement and education. The clinic is dotted with posters explaining the symptoms of malaria and the biology of mosquitoes. Earlier this morning, Honey Moon, a Karen woman who is one of Nosten’s oldest colleagues, knocked on the doors of all the absentees from the last round to persuade them to come for tests. As a result, 16 newcomers turned up for treatments, bringing the team closer to the full 393. Nosten is pleased. “In this village, I’m quite optimistic that most people will be free of the parasite,” he says.

Another village down the river is proving more difficult. They are more socially conservative and have a poorer understanding of healthcare. There are two factions of Karen there, one of which is refusing to take part to spite their rivals. “It’s a good lesson for us,” says Nosten. “These situations will be elsewhere.” Eliminating malaria is not just about having the right drug, the deadliest insecticide, or the most sensitive diagnostic test. It is about knowing people, from funders to villagers. “The most important component is getting people to agree and participate,” says Nosten. It matters that he has been working in the region for 30 years, that the Shoklo unit is a familiar and trusted name in these parts, that virtually all his team are Karen. These are the reasons that give Nosten hope, despite the lack of political will.

If the strategy looks like it is working after a year, they will start scaling up. Eventually, they hope to cover the entire sinuous border. I ask Nosten if he would ever consider leaving. He pauses. “Even if I wanted to go somewhere else, I’m more or less a prisoner of my own making,” he says. He would need to find a replacement first – a leader who would command respect among both the Karen and malaria researchers, and would be willing to relocate to a place as remote as Mae Sot. It is hard to imagine a second person who would tick all those boxes. Surrounded by airborne parasites, spreading resistance, and border-hopping refugees, François Nosten is stuck. He would not have it any other way.


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Here’s What Happens Inside You When a Mosquito Bites

The video above shows a brown needle that looks like it’s trying to bury itself among some ice-cubes. It is, in fact, the snout of a mosquito, searching for blood vessels in the flesh of a mouse.

This footage was captured by Valerie Choumet and colleagues from the Pasteur Institute in Paris, who watched through a microscope as malarial mosquitoes bit a flap of skin on an anaesthetised mouse. The resulting videos provide an unprecedented look at exactly what happens when a mosquito bites a host and drinks its blood.

For a start, look how flexible the mouthparts are! The tip can almost bend at right angles, and probes between the mouse’s cells in a truly sinister way. This allows the mosquito to search a large area without having to withdraw its mouthparts and start over.

“I was genuinely amazed to see the footage,” says James Logan from the London School of Hygiene and Tropical Medicine, who studies mosquitoes. “I had read that the mouthparts were mobile within the skin, but actually seeing it in real time was superb. What you assume to be a rigid structure, because it has to get into the skin like a needle, is actually flexible and fully controllable. The wonders of the insect body never cease to amaze me!”

From afar, a mosquito’s snout might look like a single tube, but it’s actually a complicated set of tools, encased in a sheath called the labium. You can’t see the labrum at all in the videos; it buckles when the insect bites, allowing the six mouthparts within to slide into the mouse’s skin.

Four of these—a pair of mandibles and a pair of maxillae—are thin filaments that help to pierce the skin. You can see them flaring out to the side in the video. The maxillae end in toothed blades, which grip flesh as they plunge into the host. The mosquito can then push against these to drive the other mouthparts deeper.

The large central needle in the video is actually two parallel tubes—the hypopharynx, which sends saliva down, and the labrum, which pumps blood back up. When a mosquito finds a host, these mouthparts probe around for a blood vessel. They often take several attempts, and a couple of minutes, to find one. And unexpectedly, around half of the ones that Choumet tested failed to do so. While they could all bite, it seemed that many suck at sucking.

The video below shows what happens when a mosquito finally finds and pierces a blood vessel. On average, they drink for around 4 minutes and at higher magnifications, Choumet could actually see red blood cells rushing up their mouthparts. They suck so hard that the blood vessels start to collapse. Some of them rupture, spilling blood into the surrounding spaces. When that happens, the mosquito sometimes goes in for seconds, drinking directly from the blood pool that it had created.

When the mosquitoes were infected with the Plasmodium parasites that cause malaria, they spent more time probing around for blood vessels. It’s not clear why—the parasites could be controlling the insect’s nervous system or changing the activity of genes in its mouthparts. Either way, the infected mosquitoes give up much less readily in their search for blood, which presumably increases the odds that the parasites will enter a new host.

Many hours after a bite, Choumet’s team found Plasmodium in the rodents’ skin, huddled in areas that were also rife with the mosquito’s saliva. The mosquito starts salivating as soon as it probes the mouse’s skin, releasing substances that prevent blood vessels from constricting, stop blood from clotting, and prevent inflammation. Sometimes, Choumet could see the saliva as small bubbles that hung around the tips of the mouthparts. And even after the mosquito stops feeding, pockets of saliva linger in the lower layers of the skin. Plasmodium parasites seem to stay in the same place—perhaps they work together with the salivary chemicals to suppress the mouse’s immune system.

The team also tested “immunised” mice, which were loaded with antibodies that recognise a mosquito’s saliva. “Some people, especially in Africa and Asia, are bitten several times every day, so we wanted to know if mosquitoes behaved differently when they bit animals that were immunised against their saliva,” says Choumet.

She found that the antibodies reacted with the insect’s saliva during a bite, forming noticeable white clumps at the tips of the probing mouthparts. This clogged up smaller blood vessels, which stopped the mosquitoes from drinking from them. But the insects got around this problem by probing around for longer, and by hitting the largest blood vessels.

Beyond the stunning videos, these discoveries are unlikely to lead to new ways of preventing or treating malaria by themselves. However, they do tell us a lot more about the event that kicks off every single malaria case—a mosquito bite. It’s a resource that other researchers will undoubtedly use. “I have submitted  a grant application to investigate  aspects of the interactions between mosquitoes, hosts and parasites,” says Logan. “The techniques and discoveries from this paper are very exciting to me, and will be of value to future activities of my own research group.”

Hat-tip to James Logan for alerting me to the story via Twitter, and inspiring the headline!

Reference: Choumet, Attout, Chartier, Khun, Sautereau, Robbe-Vincent, Brey, Huerre & Bain. 2012. Visualizing Non Infectious and Infectious Anopheles gambiae Blood Feedings in Naive and Saliva-Immunized Mice. PLoS ONE http://dx.doi.org/10.1371/journal.pone.0050464

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Mosquitoes temper severity of malaria

In labs around the world, scientists study malaria by injecting rodents with Plasmodium—the parasites that cause the disease. These experiments are necessary but also artificial. In the wild, the needle that spreads malaria isn’t a hypodermic syringe, but a mosquito’s snout.

Both delivery routes end in infection, but they have very different effects. Philip Spence from the National Institute for Medical Research in London has found that malarial parasites cause less severe disease if they have spent time in a mosquito—that is, they become less virulent. Something in them changes so that when they move into a mammal, they trigger a stronger immune response, grow less well and cause milder symptoms.

A word of caution: This doesn’t mean that mosquitoes are protecting us from malaria. They’re not suddenly our allies. Instead, Spence’s study shows that they can temper the lethality of the disease that they spread. They’re not just a vector but a regulator.

It was in 1897 when Nobel prize-winner Ronald Ross found Plasmodium in the stomach of a mosquito that had bitten a malaria patient, and went on to show the parasite’s full life cycle. Now, 118 years later, “Spence has come full circle by uncovering a new way in which mosquitoes play a central role in malaria—not just by transmitting the disease but by modifying its severity too,” says Sarah Reece from Edinburgh University.

“I don’t remember being as excited about a basic malaria paper for a long time,” says Andrew Read from Pennsylvania State University, who studies the evolution of infectious diseases.

The study

When a malarial mosquito bites a human, Plasmodium travels down its snout into the bloodstream of its new host. Its first stop is the liver, where it reproduces before re-entering the blood and infecting red blood cells. Since the blood-stage is when the parasite causes disease, scientists often bypass the rest of the complicated life-cycle. They just transfer parasites from one animal’s blood to another’s. If you do this repeatedly—a technique called serial blood passage—the parasite seems to become more virulent, although no one knew why.

Jean Langhorne, who led the new research, was originally motivated by criticisms that these mouse experiments weren’t relevant enough for human diseases. “We wanted to make our mouse model as relevant as possible, so we wanted to transmit the parasite as naturally as possible,” she says.

Spence, a postdoc in her lab, worked with Plasmodium chabaudi—a species that causes malaria in rodents but produces similar symptoms to human malaria. When injected directly into a mouse’s blood, P.chabaudi grew rapidly and caused severe chills, weight loss, fatigue and liver damage. But when transmitted by a mosquito, it grew slowly and the mice barely suffered. They became anaemic, but not much else.

The same thing happens to the parasites that cause sleeping sickness after passing through their  tsetse fly vectors. “There was a feeling that this happens in malaria too but this is the first strong evidence for that,” says Read.

The mosquito-borne parasites trigger a very different immune reaction from the mice than those that are injected directly. The rodents marshal a bigger squadron of white blood cells to recognise the invaders and attack them with antibodies. At the same time, these cells produce fewer of the inflammatory molecules that are linked to severe disease.

But it’s not just about the host. Spence found that a spell in a mosquito changes the activity of around 10 percent of the parasite’s genes. These include the majority of the pir genes, which produce proteins that are recognised by the host’s immune system. The upshot is that the mice are better able to control their parasites if delivered by mosquito rather than syringe… but largely due to changes in the parasites themselves.

What does it mean?

Read says that the study reveals two sides to Plasmodium. The parasites have genes that trigger a strong immune response, which leads to mild, long-lasting infections and less collateral damage for their hosts. But they must also have genes that trigger a stronger short-term infection—that’s what you see if you inject them directly into the blood.

“Within its genome, the parasite has the capacity to produce two very different infection profiles,” Read says. Short, strong infections are a good strategy in an epidemic, when hosts are plentiful. But in long dry seasons, when there might not be any mosquitoes for months, “natural selection will produce infections that grumble on for a long time without making the host very sick. There won’t be just one type of malaria.”

But Margaret Mackinnon, who studies malaria at the KEMRI-Wellcome Research Programme in Kenya, cautions against thinking that the “parasite uses the vector to modify its virulence in order to stop itself from killing the host”. To her, it’s more that the  mosquito puts a natural brake on the parasite. Serial blood passages remove that brake and things go hay-wire. “But don’t worry, because this can never happen in nature,” says Mackinnon.

Indeed, some scientists say that the mosquito results only stand out because they use parasites that have already gone through several serial blood passages. “Blood passage is totally abnormal,” says William Collins from the Center of Disease Control. He praises the paper but disagrees that a stay in a mosquito reduces the parasites’ virulence. “Rather, mosquito transmission restores it to near that of the original level,” he says.

Sure, blood passage artificially inflates the parasite’s powers and in the wild, mosquitoes might reduce virulence to a much lesser extent. But “if the effects are smaller in a natural situation, it doesn’t mean that they aren’t important,” says Mackinnon. “Natural selection operates on small as well as large differences.”

Regardless of the interpretation, it’s clear that the study raises more questions than it answers. “There’s no question that it’s a very cool paper, but it feels like it’s a start of something,” says Read. For example, we only know that the parasite activates genes that affect the host’s immune system. But when? In the mosquito? In the liver? In the blood? And Reece wants to know if these genes interact with the mosquito’s own immune system, rather than just the mammal’s.

And, perhaps most importantly, how does the mosquito modify the parasite? Mackinnon puts forward three possibilities. It could be that a small (and genetically narrow) force of parasites makes it out of the mosquito, and they’re more easily handled by the immune system. Alternatively, virulent mutants might get weeded out during the infection because they’re harder to transmit. Or maybe the mosquitoes could trigger “epigenetic” changes that alter how the parasite’s genes are used without changing the sequences of the underlying DNA. Langhorne strongly suspects that the epigenetic explanation is right, and she’s planning to test it.

Reference: Spence, Jarra, Levy, Reid, Chappell, Brugat, Sanders, Berriman & Langhorne. 2013. Vector transmission regulates immune control of Plasmodium virulence. Nature http://dx.doi.org/10.1038/nature12231

More on malaria:

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Malaria parasites evolve in vaccinated mice to cause more severe disease

Curing disease is really a matter of outfoxing evolution. When we assault bacteria or viruses or cancer cells with drugs, they evolve ways of resisting those drugs. We attack, they counter-attack. Take malaria: the Plasmodium parasites that cause the disease have repeatedly evolved to resist our best anti-malarial drugs. The mosquitoes that carry the parasites have evolved to resist the insecticides we poison them with. And now, Victoria Barclay from Pennsylvania State University has found that some malaria vaccines could drive Plasmodium to become even deadlier than it is now.

Several malaria vaccines are in development, but none have been licensed yet. Barclay vaccinated mice with a protein that’s found in several of these vaccines, and then exposed them to Plasmodium. After a few generations, the parasite became more ‘virulent’ – that is, it caused more severe disease. And it did so via an evolutionary escape route that is rarely considered.


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Engineering mosquito gut bacteria to fight malaria

A malarial mosquito is a flying factory for Plasmodium – a parasite that fills its guts, and storms the blood of every person it bites. By hosting and spreading these parasites, mosquitoes kill 1.2 million people every year.

But Plasmodium isn’t the only thing living inside a mosquito’s guts. Just as our bowels are home to trillions of bacteria, mosquitoes also carry their own microscopic menageries. Now, Sibao Wang from Johns Hopkins Bloomberg School of Public Health has transformed one of these bacterial associates into the latest recruit in our war against malaria. By loading it with genes that destroy malarial parasites, Wang has turned the friend of our enemy into our friend.

Many groups of scientists have tried to beat malaria by genetically modifying the species of mosquito that carries it – Anopheles gambiae. Marcelo Jacobs-Lorena, who led Wang’s new study, has been at the forefront of these efforts. In 2002, his team loaded mosquitoes with a modified gene so that their guts produce a substance that kills off Plasmodium.


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Skin bacteria affect how attractive we smell to malarial mosquitoes

Your skin is teeming with bacteria. There are billions of them, living on the dry parched landscapes of your forearms, and the wet, humid forests of your nose. On your feet alone, every square centimetre has around half a million bacteria. These microbes are more than just passengers, hitching a ride on your bodies. They also affect how you smell.

Skin bacteria are our own natural perfumers. They convert chemicals on our skin into those that can easily rise into the air, and different species produce different scents. Without these microbes, we wouldn’t be able to smell each other’s sweat at all. But we’re not the only ones who can sniff these bacterial chemicals. Mosquitoes can too. Niels Verhulst from Wageningen University and Research Centre has just found that the bacteria on our skin can affect our odds of being bitten by a malarial mosquito.


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Buttery perfume deters mosquitoes by overloading their sense of smell

Every time you exhale, you send out a beacon to hungry mosquitoes. These vampires follow their noses. They’re exquisitely sensitive to carbon dioxide in the air, and can follow faint traces over long distances. Constant streams of the gas won’t do – the mosquitoes are waiting for the rhythmic pulses of carbon dioxide, such as those given off by a breathing human. Once they find such a plume, they fly headlong into it, tracking it back to its blood-filled source.

This tracking ability makes it hard to avoid the attention of mosquitoes, or the diseases that they transmit with their bites. You could simply hold your breath to avoid giving off any telltale gases and because you would quickly die, malaria and dengue fever would not be a problem.

But there is a better way. Stephanie Lynn Turner and Nan Li from the University of California, Riverside, have found a cocktail of chemicals that can turn a mosquito’s senses against it. The chemicals target the very neuron that mosquitoes use to detect carbon dioxide, causing them to go berserk. They fire so wildly that they become useless. By disabling a mosquito’s guidance system, Turner and Li have found a way of making these human-seeking missiles go careening off course.


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Fungus loaded with scorpion toxin to fight malaria

Meet our newest potential weapon against malaria – a fungus loaded with a chemical found in scorpion venom. Metarhizium anisopliae is a parasitic fungus that infects a wide variety of insects, including the mosquitoes that spread malaria. Their spores germinate upon contact and the fungus invades the insect’s body, slowly killing it. Now, Weiguo Fang from the University of Maryland has modified the fungus to target the malaria parasites lurking inside the mosquitoes.

Fang loaded the fungus with two chemicals that attack the malaria parasite Plasmodium falciparum. The first is a protein called SM1 that prevents the parasites from attaching to the mosquito’s salivary glands. By blocking Plasmodium‘s path, SM1 stops the parasite from travelling down the mosquito’s mouthparts into the people it bites. The second chemical is scorpine – a toxic protein wielded by the emperor scorpion, which kills both bacteria and Plasmodium. This double whammy of biological weapons slashed the number of parasites in mosquito saliva by 98%.


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One jump from gorillas to humans – the origin of malaria


Several million years ago, Plasmodium falciparum – the parasite that causes most cases of human malaria – jumped into humans from other apes. We’ve known as much for decades but for all this time, we’ve pinned the blame on the wrong species. A new study reveals that malaria is not, as previously thought, a disease that came from chimpanzees; instead it’s an unwanted gift from gorillas.


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Beer makes humans more attractive to malarial mosquitoes

We’ve all heard about “beer goggles”, the mythical, invisible eyewear that makes everyone else seem incredibly attractive after a few pints too many. If only beer had the reverse effect, making the drinker seem irresistibly attractive. Well, the good news is that beer does actually do this. The bad news is that the ones who are attracted are malarial mosquitoes.

Anopheles gambiae (the mosquito that transmits malaria) tracks its victims by their smells. By wafting the aromas of humans over thousands of mosquitoes, Thierry Lefevre found that they find the body odour of beer drinkers to be quite tantalising. The smell of tee-total water drinkers just can’t compare. The somewhat quirky conclusion from the study, albeit one with public health implications, is that drinking beer could increase the risk of contracting malaria.

Lefevre recruited 43 men from Burkina Faso and sent them individually into one of two sealed, outdoors tents. One tent was kept unoccupied. In the second, the volunteer had to drink either a litre of water (just shy of two pints) or a litre of dolo (a local 3% beer and the country’s most popular alcoholic drink). A fan pumped air from the tents, body odour and all, into the two forks of a Y-shaped apparatus. Both branches met in a third arm, which ended in a cup full of mosquitoes. The insects had to decide which branch of the Y to fly down and two pieces of gauze trapped them in their chosen path (and saved the volunteers from an infectious bite).

Lefevre showed that the smell of a beer drinker, 15 minutes after chugging his litre, increased the proportion of mosquitoes inclined to fly into the tubes, and the proportion (65%) who headed down the beer-scented fork.  The smell of water-drinkers had no effect, nor did the smell of the occupied tent before its inhabitant started drinking.


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One parasite to rule them all – Wolbachia protects against mosquito-borne diseases

This is an updated version of the first post I wrote this year. The scientists in question were looking at ways of recruiting bacteria in the fight against mosquito-borne diseases, such as dengue fever. They’ve just published new results that expand on their earlier experiments.

Mosquitoes are incredibly successful parasites and cause millions of human deaths every year through the infections they spread. But they are no match for the most successful parasite of all – a bacterium called Wolbachia. It infects around 60% of the world’s insect species and it could be our newest recruit in the fight against malaria, dengue fever and other mosquito-borne infections.

Lolbachia1.jpgWolbachia doesn’t usually infect mosquitoes but Scott O’Neill from the University of Queensland is leading a team of researchers who are trying to enlist it. Earlier this year, they published the story of their first success. They had developed a strain that not only infects mozzies, but halves the lifespans of infected females. Now, as the year comes to an end, they’re back with another piece of good news – their life-shortening bacteria also guard the mosquitoes from other infections.

It protects them against a species of Plasmodium, related to the parasite that causes malaria in humans, as well as the viruses responsible for dengue fever and Chikungunya. Infected insects are less likely to carry parasites that cause human disease, and those that do won’t live long enough to spread them. It’s a significant double-whammy that could have a lot of potential in controlling mosquito-borne diseases.


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Genetically-modified mosquitoes fight malaria by outcompeting normal ones


Blogging on Peer-Reviewed ResearchFighting malaria with mosquitoes seems like an bizarrely ironic strategy but it’s exactly what many scientists are trying to do. Malaria kills one to three million people every year, most of whom are children. Many strategies for controlling it naturally focus on ways of killing the mosquitoes that spread it, stopping them from biting humans, or getting rid of their breeding grounds.

anophelesgambiaemosquito.jpgBut the mosquitoes themselves are not the real problem. They are merely carriers for the true cause of malaria – a parasite called Plasmodium. It suits neither mosquitoes nor humans to be infected with Plasmodium, and by helping them resist it, we may inadvertently help ourselves. With the power of modern genetics and molecular biology, scientists have produced strains of genetically engineered mosquitoes that cannot transmit the malarial parasite.

These ‘GM-mosquitoes’ carry a modified gene – a transgene – that produces chemicals which interfere with Plasmodium‘s development. Rather than being suitable carriers, the bodies of the modified mosquitoes spell death for any invading Plasmodium.

But scientists can’t very well change the genes of every mosquito in the tropics. To actually reduce the burden of malaria, the genetic changes that induce malaria resistance need to be spread throughout the mosquito population. The easiest way to do this is, of course, to let the insects do it themselves. And Mauro Marrelli and colleagues from the Johns Hopkins University have found that they are more than up to the task.


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Size matters for mosquitoes but medium-sized males do better

Last year, I blogged about an ironic public health strategy – controlling malaria with mosquitoes. The mozzies in question are genetically engineered to be resistant to the malaria parasite, Plasmodium. The idea is that these GM-mosquitoes would mate with wild ones and spread their resistance genes through the natural population.

Anopheles.jpgThe approach seems promising but it relies crucially on the ability of the resistant males to successfully compete for the attentions of females in wild populations. The 1960s and 1970s witnessed several failed attempts to control malaria by swamping natural populations with sterile males released en masse. And while these letdowns had been blamed on ignorance about mosquito mating, this area of research has gone untouched until now.

A new study, which I’ve reported on in New Scientist, shows that size does indeed matter for mosquitoes, but it’s the average Joes that get the girls. Kija Ng’habi, a young Tanzanian MSc student, reared males of different size by controlling their diet as larvae, and pitted them against each other for the attentions of females in a cage.

He found that the average-sized males had twice as much sex as the smaller males. But amazingly, they also secured six times as many matings as the biggest ones, despite having smaller wingspans, lower energy reserves and shorter lifespans. In the long run, the longer lives of the big mozzies are unlikely to make up for their comparative failure to mate with females.