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This week's programme script

Mosquito!
Thursday, 15th October 1998


NARRATOR (JULIET STEVENSON): It is the most dangerous insect in the world. A hundred years ago scientists began an astonishing campaign to wipe it off the face of the planet, but it fought back and today the disease it carries kills millions.

DR. STEPHEN HOFFMAN (Us Naval Medical Research Institute): It’s estimated that 10,000 children die every single day of malaria.

PROF. STEVEN MESHNICK (Michigan State University): We’ve thrown everything we’ve had at it, we’ve put our best scientists on it and today there are more people dying of malaria than ever before.

DR NICHOLAS WHITE (Mahidol Hospital Thailand): This huge mortality is held in check by drugs, but we’re losing them. If we don’t get a new and effective treatment it is going to be a disaster.

NARRATOR: Now a wonderful new discovery might save humanity from the deadly bite of the mosquito. To study mosquitoes in the lab requires unusual dedication.

DR WILLIAM TAKKEN (University of Wachiningen): The trouble with keeping mosquitoes is that you have to feed them. The males are being fed on sugar water which is in this bottle here in the middle of the cage and you just see a male landing on it, but the females need something totally different. They only like blood and preferably in this case human blood. I’m giving them the chance to feed on my arm twice a week. With mosquitoes only the, the females take blood. They have mouth parts that are specially adapted to this kind of feeding behaviour. As the mosquito lands on the skin it inserts its mouth parts until they find a blood vessel. Subsequently the wall of the blood vessel is being damaged and a pool of blood erupts. Now a mosquito can prevent this blood from being clotted by injecting from its saliva an anti-coagulant, but it is an excellent meal for them because basically it is concentrated protein which allows them to develop eggs much more efficiently than let’s say a butterfly. In some places of the world mosquito densities are so high that if you go outside you may die as a result of blood loss because of the many mosquitoes that come and take a blood meal.

NARRATOR: A female mosquito’s desire for blood is almost narcotic. She will feed on it until she can hardly fly and afterwards she must rest, exhausted, for a whole day. We humans pay a terrible price for this addiction. The symptoms of malaria are horrific - a fever so severe it cooks the internal organs, heart failure, suffocation of the brain and coma. In parts of Africa half the children die of malaria. Across the Tropics, in South America, India and the Far East it is one of the greatest killers. This year 2 million people will die from the disease, but this is a disease that long ago scientists said they would eradicate. Every attempt so far has failed and instead things are getting worse. Behind this failure lies the story of a century long battle against nature, a battle that is about to begin again. For thousands of years malaria was rampant across the world including most of Europe, but no-one knew what caused it.

DR MARY DOBSON (Wellcome History of Medicine Unit): Up until the end of the 19th-century malaria was a really mysterious disease. Many people associated it with foul smells, with the bad airs of stagnant marshes. The word malaria comes from the Italian mal-aria - bad airs - and this became very much a preoccupation that people would visit countries where they would see these horrible, foul smelling marshes, and this gave them the idea that the mal-aria, the miasmas, the mists of these marshes actually caused the disease.

NARRATOR: Then the mystery deepened. Scientists discovered that the blood of people with malaria was full of parasites. It was these that caused the disease. Everyone assumed the parasites must come from the marshes, but when they looked the parasites were nowhere to be found.

MARY DOBSON: Nobody could work out what the mechanism was to take the parasite into the human and how from one human to another the disease malaria, the malaria parasite, could be transmitted. This was the mystery that scientists were out to solve.

NARRATOR: There were many theories. Some scientists said it was in the air, others in the drinking water and some even wondered if it might be transmitted sexually. Then one British doctor heard an even more outlandish theory. In the 1890s Ronald Ross was in India treating soldiers with malaria when he came across a paper that suggested mosquitoes might spread the parasite. Malaria experts dismissed the idea as ludicrous. But Ross, a mere GP, set out to test the theory in what would become one of the most important experiments in the history of medicine. Nowadays it can only be done in a high security laboratory. He collected mosquitoes and fed them with the blood of people infected with malaria parasites. He wanted to see what happened to the parasite once it was inside the mosquito’s body. It seemed impossible that a creature that lived in warm human blood could also survive inside a cold-blooded insect. Mosquitoes were considered so unimportant that hardly anyone had bothered to dissect them and Ross knew next to nothing about insects, so his work would take him 2 years. He tried several species of mosquitoes but the parasites simply died inside them. Then he tried one of the most common species of all - anopheles. When Ross dissected this he found something no-one had ever seen before. In its gut was cyst-like shapes, eggs of malaria parasites. Ross had proved that the parasite could survive inside a mosquito, but how did the parasite then get back into humans? He returned to his dissection to see what happened next. He was amazed to find that the eggs had hatched releasing thousands of rod-like parasites into the mosquito. He watched as the parasites migrated through the wall of the mosquito’s gut into its body. They seemed to know exactly where they were going. They wriggled their way through the body up into the head. Then one by one into the salivary glands. They were ready to be injected when the mosquito next fed.

MARY DOBSON: It seems, looking back, so obvious. We’re so familiar now with the transmission of many diseases, including malaria, by mosquito bites, but that was a really, really major scientific breakthrough to know that the mosquito could inject the parasite into the human bloodstream through that biting process.

NARRATOR: Ross had uncovered the key role of the mosquito in what is one of the most intricate life cycles in biology. If an anopheles mosquito feeds on someone infected with malaria parasites it takes them into its own body. When the infected mosquito feeds again it injects the parasites into another human being. The parasite is a protozoa. Inside the human body it mutates and destroys red blood cells. This causes the disease we know as malaria. The life cycle is an elaborate chain. Break one link and the parasite cannot spread.

STEPHEN HOFFMAN: When Ross made this discovery, for which he was eventually awarded the Nobel Prize, it provided the possibility of actually beginning to prevent this disease which had ravaged humanity for thousands of years. This was really one of the first examples of where an understanding of the life cycle, meaning how a disease is transmitted, could actually be applied to preventing that disease. Now that it was known that mosquitoes transmitted malaria one could then attack the mosquitoes and in fact Ross set out after that discovery to cure the world of malaria.

MARY DOBSON: He seized this breakthrough as now the answer to the prevention of malaria. It’s really very simple. If mosquitoes transmit malaria, what better than to kill the mosquitoes. That is his message to the world, to the malarial countries of the world - kill the mosquitoes.

NARRATOR: An extraordinary battle against nature began. They started with the mosquitoes breeding grounds. The larvae lived underwater, so marshes were drained. Slow-moving rivers were cleared and oil was spread on the surface to suffocate them. Then they brought in the bombs.

MAN: Watch. Here it goes. This well engineered blasting is a thunderclap of doom for millions upon millions of unborn mosquitoes.

NARRATOR: There were some notable successes. In the 1930s Mussolini was able to declare the area round Rome malaria-free for the first time in history. But keeping marshes drained was a constant battle. What was really needed was something that would get rid of mosquitoes once and for all. One group of people came up with the answer.

STEPHEN HOFFMAN: Every military campaign that our forces, meaning US forces, have been involved in when we were engaged in military campaigns where malaria was transmitted we have always had more casualties to malaria than to hostile fire.

NICHOLAS WHITE: In any tropical theatre of war you, as an army, always lose more soldiers to malaria than bullets, so it makes sense for an army to be interested in malaria and ways of protecting its soldiers.

NARRATOR: The American military had long devoted huge resources to disease research. During the Second World War they made malaria their top priority. They began to test thousands of compounds to see if they could come up with a uniquely powerful insecticide. They came up with a legend. It destroyed the nervous system of mosquitoes so completely that minute quantities were deadly. Sprayed onto surfaces it was still killing mosquitoes a year later and it was cheap. Even the poorest country in the world would be able to afford it. Its name was DDT.

WILLIAM TAKKEN: This success was then taken as justification to start a worldwide eradication programme of malaria whereby the entire world actually would be sprayed with an insecticide to get rid of the mosquitoes and subsequently get rid of the malaria.

NARRATOR: In the optimism of the post-war years the new World Health Organisation came up with a bold plan - to eradicate malaria completely. Most of the staff and money at WHO were devoted to the task and they said malaria would be gone by the 1990s. DDT was to consign it to the history books. The strategy was simple - to break the life cycle of the disease on a global scale by wiping out mosquitoes. It was a huge undertaking. No corner of the world was ignored, no home too humble to receive attention.

NICHOLAS WHITE: They were able to completely remove the disease from Europe, North America and Russia. The incidence of the disease fell dramatically in many parts of the Tropics as well.

NARRATOR: Success spurred them on. It was the mosquito’s darkest hour. No hiding place was secure.

ARCHIVE FILM NARRATION: There were also breeding places in pot-holes high up in the mountains. Local mountaineers were enlisted to deal with them.

NICHOLAS WHITE: This was a fantastic development and it gave them hope that they could actually eradicate the disease completely from the world.

STEPHEN HOFFMAN: It was dramatically reduced in South America, it was dramatically reduced in India and Sri Lanka where it, where there had been in India 80 million cases prior to eradication and they were able to reduce it down to 50,000 cases.

NARRATOR: Everything seemed to be going to plan.

ARCHIVE FILM NARRATION: Our children will be the first generation freed from the enslaving fever.

NARRATOR: Malaria was being described as a disease of the past. But then the mosquito fought back.

WILLIAM TAKKEN: Mosquitoes are remarkably resilient insects. One female can produce up to 1,000 offspring in a lifetime and in a very few weeks you can have millions of offspring from that one individual mosquito female. If one of these offspring happens to be resistant against an insecticide you can imagine that being so highly fertile within a very short period you can get the development of totally resistant insect populations. From the beginning people should have realised that it would never have been feasible to spray so many areas simultaneously and avoid the development of insecticide resistance.

NARRATOR: DDT began to fail and as the mosquito returned so did malaria.

STEPHEN HOFFMAN: One went from a situation where there were a handful of cases in Sri Lanka and thousands of cases in India to a situation where they went to millions of cases.

NARRATOR: As malaria rebounded scientists came up with new insecticides but resistance built up to them too and they were all hundreds of times more expensive than DDT, much too expensive for a global eradication campaign. In 1969, utterly demoralised, the World Health Organisation finally admitted it could never win the battle against the mosquito. They would have to think of another way to beat malaria. The mosquito had defeated them. There is one corner of the world where the battle against the mosquito continues to this day and here it’s a huge success. If you want to see what it takes to fight mosquitoes in a tropical climate you have to come to Florida.

TOM SAVAGE (Lee County Mosquito Control): Well in the past in one mosquito trap on Santa Belle one night they trapped 365,000 mosquitoes. If you go out now in that same place and put that same trap out you might trap 15 mosquitoes.

NARRATOR: Florida had a serious malaria problem until the 1940s. Spraying with DDT stamped it out, but when DDT failed the Americans could afford to keep fighting. They simply bought the new, more expensive insecticides and sprayed them 24 hours a day, everywhere, and when each insecticide failed the insect killers of Florida bought the next chemical, no matter the cost. It’s been a constant battle to outwit the mosquito’s ability to adapt. It requires some serious hardware.

MAN: Mosquito 62 Mike Roger, report from your spray area.

TOM SAVAGE: We eradicated malaria here in the 40s and health concerns for our citizens here is the number one reason that mosquito control exists. We don’t want malaria to invest our county. We have a very comprehensive programme here at Lee County Mosquito Control. We send out field inspectors in small helicopters to areas that are known to breed mosquitoes and when they find small concentrations of mosquito larvae we’ll take care of them right there on the spot. When we find large areas that are breeding we’ll send out our Hewies - those are Vietnam era helicopters. They’re pretty much battle tanks too.

(ACTUALITY CHAT)

It’s only after the mosquito population hatches out and the adults fly that we have the use of DC3s. When we end up using the DC3s were losing the war against the mosquito larvae. But we still have the means to kill them once they get to that flying stage.

OK, the insecticide’s loaded, we’re ready for take-off.

We are a group of people that come together for one cause and that’s to fight mosquitoes. We have aircraft, we have helicopters, we have trucks, certainly the personnel we need to fight this war and for the most part we win.

NARRATOR: This is what it takes to keep mosquitoes under control in a tropical environment - $300 million a year in Florida alone. It’s money and equipment which the countries most affected by malaria can only dream of. No other country could afford the fight the mosquito. After spraying was abandoned, across the developing world the mosquito returned - with a vengeance. But by now scientists had thought of a different way to beat malaria. This time, rather than attacking the mosquito, they decided to kill the parasite it carries instead. This next battle against nature was to prove just as difficult and take an unexpected turn, one in which science and politics clashed - with disastrous results.

NICHOLAS WHITE: The malaria parasite is a clever beast. It evades the normal immune mechanisms that we have in our bodies to protect us against infectious agents. It lives inside red blood cells and so the body only sees the blood cell, it doesn’t see the parasite inside for most of the time, and when it does show itself it’s not recognised. You begin to recognise one sort of parasite and then it becomes another sort of a parasite. It’s a dangerous adversary, not to be under-estimated.

STEPHEN HOFFMAN: It has a stage in your bloodstream when it’s injected, another stage that lasts for a week in your liver, another stage in your bloodstream that causes disease and another stage that’s picked up by mosquitoes where it develops during two weeks. A virus like the virus that causes AIDS, HIV virus or Dengue virus, or the bacteria that causes typhoid fever don’t have this complexity.

NARRATOR: Unable to develop a vaccine scientists believe they could defeat this complex enemy with a different weapon - drugs. The effectiveness of a drug depends on the molecules that make it up. There has long been one drug whose molecules killed malaria parasites - the drug quinine.

MARY DOBSON: Quinine had been used for several hundreds of years. It was a wonderful, a wonderful gift of nature coming from the cinchona plant in South America. It had been used quite widely but once quinine had been extracted from the plant the drug itself was expensive.

STEVEN MESHNICK: Quinine is a very good drug but in order to cure malaria with quinine you have to take large doses of it for long periods of time and there are lots of side-effects. People get quite ill from taking quinine, so it’s not the kind of drug you can use routinely.

NARRATOR: So in the 1940s scientists took the molecules of quinine and adapted them to make a whole family of cheaper and safer anti-malarial drugs. The first and best was chloraquine. By the 1950s it was the most commonly taken drug in the world after aspirin and it saved millions of lives. But the parasite had a weapon of its own. Inside the mosquito the parasite was evolving. In the cool comfort of the insect’s body the protozoa reproduces. As it multiples it constantly creates new mutations of itself, each genetically different from the other. It was this that would defeat us, for it was only a matter of time until the parasite evolved into a new form that could recognise and resist the drugs and then the resistant parasite inside the mosquito spread across the world.

STEPHEN HOFFMAN: Unfortunately beginning in Columbia and in Thailand in the late 1950s and early 1960s resistance to chloraquine began to develop. Resistance has now spread essentially over the entire globe. The drug which was the best drug that we ever had for malaria is almost useless in most places. What we have found is that as soon as we develop a new drug the parasite, this incredibly complex infectious agent, learns how to become resistant to that drug.

NARRATOR: As each drug failed a new one replaced it and failed even quicker. There was a fatal flaw with all of them. All the molecules were chemically almost identical. They were all based on the same original quinine molecule. And parasites that could recognise one molecule could recognise them all.

DR ARNOLD BROSSI (World Health Organisation (78-89)): At the end of the 1970s we got very much worried at the WHO steering committee that, that we had no other drugs which could be recommended once resistance had been developed and we were eagerly looking for something entirely new, something novel.

NICHOLAS WHITE: We were running out of drugs, we were very anxious to find new anti-malarials and so any, anything which looked promising was of interest.

NARRATOR: By the end of the 1970s scientists were desperate for something to beat this parasite. What was needed was a new molecule, something so different that the parasite couldn’t recognise it. Unbeknownst to the rest of the world the molecule had already been found. It was to come from a country that had never produced an anti-malarial drug before, in one of the darkest periods of its history. The drug would prove to be spectacularly effective, but for 30 years, while millions died, it was caught in a web of intrigue. Almost defeated this time not by the mosquito or the parasite, but by human nature itself.

STEVEN MESHNICK: During the Cultural Revolution there was a very big anti-intellectual campaign. Intellectuals - professors, physicians and scientists - were suddenly considered counter-revolutionary. They were forced to leave their homes and, and take very low prestige jobs in the, in the countryside, shovelling manure or, or helping with the harvest.

CHINESE CHANTING: We have come out of school to rebel! Get rid of the capitalists within the Party! Death to Western snake spirits!

NARRATOR: In 1967 in the middle of the Cultural Revolution, Dr. Ying Li joined a group of young scientists who had answered a call from Chairman Mao himself - to solve the problem of malaria.

PROF. YING LI (Malaria Medicine Institute, Shanghai): We were forced to take time off our work for political meetings, and denunciations. We had to constantly read and sing Chairman Mao’s thoughts.

NARRATOR: Mao considered everything Western to be decadent, including medicine, so instead the scientists looked to the Chinese past for inspiration. For thousands of years herbs have played a key role in Chinese medicine, but when Ying Li and her colleagues began their search hardly any of the plants had been properly investigated. They worked their way through 200 herbs which had traditionally been used against malaria fevers. None worked. Then, finally, they tried one called qing hao how from the plant artimesia. Ying Li and her colleagues followed an ancient recipe 2,000 years old for making a kind of tea that claimed to cure malaria. They distilled the tea and added chemicals to refine it until they had isolated the active compound. Then they made a drug which they tried out on patients dying from malaria. The results were astonishing. It cleared the blood of malaria parasites quicker than any drug in history. The effect on the patients was remarkable.

YING LI: Many of the doctors sat by the patients. The sense of joy when they came round was indescribable. We had saved them from the clutches of death itself.

NARRATOR: The Chinese had discovered what the whole scientific community had been hoping for - a completely new and powerful drug against malaria. They continued to test it, refine it, perfect it, but it was years before they would tell anyone else it even existed.

STEVEN MESHNICK: By the time it was published in English it was really probably 10 years after most of the work was done. Much of the work came out in ‘79 and a large series of papers came out in 1982 in English and these reported things that had been done a long time ago.

NICHOLAS WHITE: I think I was working in eastern Thailand at the time and we got a photocopy of a, an article in the Chinese Medical Journal which was extraordinary. It described the discovery, or rediscovery, of a, a plant-derived medicine. It described the evaluation of this in the laboratory to show that it had anti-malarial activity. The structure, the chemical structure and then actual clinical trials with this new compound which suggested that it was a very active anti-malarial. It just sounded extraordinary.

NARRATOR: There was something else about qing hao su. The Chinese claimed the molecule of the drug was completely different from any other anti-malarial. It was so new the malaria parasite wouldn’t be resistant to it, but it was also so new they couldn’t fathom how it worked and so strange that many Western scientists were sceptical that it worked at all.

ARNOLD BROSSI: It’s a beautiful molecule to look at and it caught the attention of, of many, many people. It had this strange peroxide group, two oxygen attached to each other and we never have seen in medicinal chemistry something useful from this type of compound.

STEVEN MESHNICK: Well no-one had ever seen a molecule like ching how su before. It contained something called an endo-peroxide. Endo-peroxide means two oxygens and previously almost every endo-peroxide that had been found was unstable. It’s a compound that could fall apart in exposure to air and here they were claiming to have a drug that was stable and could be, could be made into a drug and would last in the body. The general feeling was this compound couldn’t possibly last long enough in the body to have an active effect.

DR MEL HEIFFER (Walter Reed Army Institute of Research): People thought well this is just a medicine man that’s working his art and who knows whether or not it really did cure malaria.

STEVEN MESHNICK: What you have to understand is that prior to this a lot of things that had been published in the Chinese literature were, were just rubbish. For example, they had claimed that they had eradicated another tropical disease called shitosomiasis when in fact they hadn’t. There was another claim that they could cure malaria with acupuncture and there was even a claim by someone that he could meditate and get DNA to twist on itself.

NARRATOR: Western scientists were keen to investigate the Chinese claims. But things did not go smoothly.

ARNOLD BROSSI: Well we tried immediately to get in touch with the Chinese and on, on different, on different levels - with scientists and with people important in the administration and the people in factories and tried to get more information about this interesting drug, qing hao su., and also we tried to get some samples of this material for testing it in our own laboratories and it was very difficult. In the early 80s it was very difficult to communicate with China.

YING LI (CHINESE WITH SUBTITLES): The foreigners seemed to be snooping. They were so arrogant, and contemptuous. They were astonished that we Chinese had managed to achieve this when it had so eluded them!

ARNOLD BROSSI: They basically didn't trust us. They thought we would like to exploit this new drug and bring it to the market in, in the western world.

NARRATOR: And there seemed good reason for the Chinese to be suspicious.

STEVEN MESHNICK: Many of the memories of the, the WHO steering committee that was responsible for anti-malaria drug development were members of the US Military. The reason for this was that the US Military has had a long and very productive history in anti-malaria drug development.

ARNOLD BROSSI: It was certainly now very helpful to have American presentation on the steering board of the World Health Organisation on malaria and especially since some of them showed up in uniform which made very obvious where they were coming from. This didn't help in getting the information we wanted to have on this exciting new drug - qing hao su..

NARRATOR: The Chinese refused to release the plant or the drug to the rest of the world. Fifteen years after they'd discovered it the drug was still unavailable to millions who needed it.

STEVEN MESHNICK: It was very frustrating in the 1980s because here was a promising compound that, that many people willing to work on, but yet we couldn't get it. It wasn't being sent out of China, so it became clear that we needed another source for the compound and in order to have another source for the compound we had to find the plant somewhere outside of China and this led to an effort by the US Military to find the plant growing somewhere.

NARRATOR: The American Army wanted to be sure they could fight anywhere in the world and so they needed to be able to protect their soldiers against malaria. If qing hao su. was the miracle malaria drug, they weren't going to put up with not having it.

MEL HEIFFER: It was somewhat troublesome to us in the beginning that we had to go all the way to China to get this herb because if we ever had a war with China we would have to go to China to get the herb for our soldiers to fight them.

NARRATOR: The American Army looked in scores of countries - in Africa, Europe and South America - but they could not find this strange Chinese herb. But then they finally stumbled upon it. It was growing along the banks of the Potomac river, the river that runs through the heart of Washington DC.

STEVEN MESHNICK: They initially found artimesia on the banks of the Potomac but soon they were finding it everywhere. It was just a weed that, that grew in, in people's gardens.

NARRATOR: With their own supply of plants the American Military could now find out if the Chinese claims for the drugs were true. Now it would be their turn to work in secret. It took another 10 years. They repeated all the Chinese experiments, refining, isolating and purifying the compound. Then they tested it on the parasite. It took until the middle of the 90s before they managed to solve the mystery that had so intrigued the Chinese. They discovered how this strange molecule worked. It was because of its instability that the molecule was able to kill malaria parasites in a remarkable new way.

STEVEN MESHNICK: Artimesia is like a bomb and there's a trigger to this bomb and the trigger turns out to be that endoperoxide bridge, those two oxygens. When those two oxygens come in contact with iron they fall apart and the whole molecule explodes and it turns out that the malaria parasite is extremely rich in iron. It lives inside the red cell which is full of iron and it concentrates its iron, so when the drug gets into the parasite it meets this iron, falls apart, produces a substance called free radicals which are extremely toxic, and kill the parasite.

NARRATOR: The molecule was so explosive it would kill parasites before they had time to recognise its structure. This meant the parasite might never develop resistance.

MEL HEIFFER: I knew now we weren't dealing with some Chinese medicine man, but we were dealing with a real scientific discovery.

NARRATOR: Qing hao su. really was the drug that everyone had been waiting for, but politics and human nature had kept it from the world for 30 long years. Finally, in the late 1990s with the Cold War over, the political climate between East and West was transformed and the two sides agreed to co-operate. Now at last the drug is being manufactured for worldwide use.

NICHOLAS WHITE: The whole process took an inordinately long period of time and we wasted years, perhaps decades, in developing these drugs which are going to be an essential part of our, of our, of our treatment. They're, they're perhaps the most important anti-malarial drugs we have.

STEPHEN HOFFMAN: We find ourself at the end of the 20th-century in a situation where there's more malaria than ever before wherein malaria is spreading into areas both at sea-level and in the mountains where it never was before, and where with the potential for global warming it has, there, there's the possibility of malaria being reintroduced into areas from which it was eradicated even in the United States and, and Europe.

NARRATOR: It is with this prospect in mind that the World Health Organisation is yet again preparing to go into battle against malaria. This year it will launch a new campaign - to halve the deaths from the disease within a decade. Again science believes it has a genuinely new weapon, a drug based on qing hao su.

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