Plasmodium falciparum is responsible for most human malaria. Credit: © WHO

The first confirmed human case of malaria dates from 450 AD. It was diagnosed last year when British researchers recovered traces of the malaria parasite's DNA from a children's cemetery just outside Rome. An epidemic of the disease may have swept through the city.

Malaria may have killed half of all the people that ever lived. And more people are now infected than at any point in history. There are up to half a billion cases every year, and about 2 million deaths - half of those are children in sub-Saharan Africa.

"It's worse than it was 50 years ago," says malaria expert Robert Desowitz of the University of North Carolina, Chapel Hill. Small wonder then that high hopes are pinned on the complete genome sequences of Plasmodium falciparum, the parasite responsible for the majority of human malaria, and Anopheles gambiae the mosquito that carries it, published this week1,2.

Bad air

Until the mid-nineteenth century, most scientists thought that noxious swamp gases caused malaria - the word means 'bad air' in Italian. The idea that mosquitoes spread the disease didn't gain momentum until Louis Pasteur's germ theory of disease raised the possibility that the mosquito might carry some form of microorganism.

The parasite was eventually spotted in human blood in 1880 by Alphonse Laveran, a French army doctor working in Algiers. In 1887 a British scientist named the beast: Plasmodium falciparum.

P. falciparum causes the most severe form of malaria; three other species of Plasmodium also cause the disease in humans. There are 170 malaria parasites in total, which mosquitoes spread between reptiles, birds and mammals. About two-dozen species of Anopheles mosquito carry human malaria.

In 1897 another Briton, Ronald Ross, an army doctor stationed in India, saw the malaria parasite inside a mosquito that had bitten a malaria patient. Looking in the gut of another mosquito, Ross saw a parasite at a different stage of its life cycle. His confirmation that female mosquitoes spread malaria - males don't bite - won him the 1902 Nobel Prize for medicine.

Life cycle

In the gut of a female mosquito, Plasmodium oocysts give birth to cells called sporozoites. These migrate to the mosquito's salivary glands, and are injected into humans. Sporozoites head for their victim's liver, where they multiply to produce another type of cells, known as merozoites. This liver stage was the last to be discovered, by a British team in 1948.

When infected liver cells burst, merozoites enter red blood cells. Inside, they divide producing sexual forms called gametocytes and asexual forms called trophozoites. When the cell ruptures the trophozoites invade yet more red blood cells. This causes fever each time.

Mosquitoes consume the gametocytes in human blood. Once inside an insect, these mate and enter her stomach wall as oocysts, which in turn produce more sporozoites.

The complexity of the parasite's life cycle is the main reason that a vaccine has so far proved impossible to produce - compounds effective against one stage miss another.

The symptoms of malaria - fever, chills and cramps - develop when the parasite emerges from the liver, a week to a month after infection. The parasite's appetite for red blood cells can cause severe anaemia. Infected red blood cells also stick to blood vessels, blocking the blood supply to the brain, with potentially fatal consequences. The body may fight off the blood-borne parasites, but the parasite can hide in the liver and re-emerge later to cause disease.

The drugs sort of work

Quinine was used to treat malaria 250 years before we knew what caused the disease. In the mid-1600s, Spanish colonists in South America discovered that the bark of the cinchona tree controls malaria - a disease that Europeans probably introduced.

Until the 1930s, quinine was the only drug effective against malaria. Because it suppresses the trophozoites that invade red blood cells, it eases the fever but does not eradicate the disease.

In 1934, German chemists invented a new antimalarial, chloroquine, which kills several Plasmodium species, and most stages of the parasite's life cycle. By the end of the Second World War, pharmacists had devised drugs effective against all stages of the parasite's life cycle. In addition, there was a powerful insecticide called DDT on the market.

For a while it looked as if this combination might defeat malaria. "When I got my PhD in 1951," Desowitz recalls, "my supervisor said: 'Malaria's dead - you'll never make a living from it'." This optimism became official policy in 1956, when the World Health Organization (WHO) launched a global campaign to eradicate malaria.

But evolution had other ideas. In the 1960s, chloroquine-resistant strains of the parasite and DDT-resistant mosquitoes became increasingly common. The temporary suppression of malaria for a decade or so had left large numbers of people susceptible to the disease. The recent backlash of malaria deaths is largely attributed to this short-lived lull.

By the end of the 60s, the WHO had admitted that eradicating malaria was impossible, and switched its goal to controlling the disease. The current WHO campaign, Roll Back Malaria, aims to halve deaths from the disease by 2010.

End game?

We now have a battery of antimalarials, including a synthetic version of quinine, mefloquine, and a group of chemicals derived from Chinese sweet wormwood, called artemisinins. A combination of drugs is regarded as the best way to prevent and treat the disease, and new drugs are needed every few years to keep pace with parasite evolution.

There's much that can be done with existing drugs, pesticides and barriers to keep out mosquitoes, says Desowitz. "Put it all together and they may spell effective control."

The mosquito and parasite genomes may lead to new drugs and control measures, and maybe even a vaccine. But Desowitz doesn't foresee the end of malaria: "I've seen a whole series of technical epiphanies, each one promising the Holy Grail. All have left some positive residue, but none have fulfilled the promise of their advocates."