The Scripps Research Institute

The Anatomy of a Parasite

"And such cities as lie well to the sun and winds, and use good waters, feel these changes less, but such as use marshy and pooly waters, and lie well both as regards the winds and the sun, these all feel it more. And if the summer be dry, those diseases soon cease, but if rainy, they are protracted...."

——Hippocrates, On Airs, Waters, an Places, 400 B.C.E.

The name malaria comes from the old French and Italian construction, "mala" + "aria," which means "bad air."

People once thought that the disease was caused by swamp gasses, since it seemed to be prevalent in wet, marshy places. Even though scientists have known for more than 100 years that malaria is caused by a microscopic parasite transmitted by a pest common to wet, marshy places—the mosquito Anopheles gambiae—the name, like the disease, persists.

Malaria is a nasty and often fatal disease and is one of the greatest scourges of modern times. Indeed, one of the greatest challenges to global public health today is the control of malaria.

Malaria Can Be Controlled

Once endemic in the southern United States and Mediterranean Europe, malaria has largely been brought under control in these areas. However, there are still occasional outbreaks, usually caused when travelers infected in another country arrive in the United States or Europe where they are bitten by a mosquito that then begins transmitting the disease to other people.

Southern California has witnessed over a dozen such cases in the last 50 years, including a large outbreak in San Diego County in August 1988 that infected 30 individuals. In total, about 1,200 cases of malaria are diagnosed in the United States each year.

But these numbers are tiny compared to the global incidence. In many parts of the world, not only is malaria a major cause of death and disability—particularly among children—it is a major drain on the economies of some of the world's most impoverished nations.

In fact, some 40 percent of the world's population lives in areas where malaria is endemic. The World Health Organization (WHO) estimates that yearly 300 million acute cases of malaria occur and more than 1 million people die of malaria each year. Most of these victims are children under the age of five.

According to the WHO, in areas of intense transmission, young children may have as many as six episodes of malaria each year; the disease consumes nearly half of annual public health care expenditures; and some 45 million years of productive human life is lost annually to the disease.

Malaria is also a contributing factor in global poverty. The disease severely impacts the gross domestic product of many of the poorest countries—the broadest measure of a nation's economy. The Wellcome Trust estimates that malaria costs the global economy the equivalent of more than $31 billion each year through lost productivity and health costs.

Lifecycle of a Killer

The parasite Plasmodium, which causes malaria, has four distinct lifecycles, and it is encountered, variously, in sporozoitic, merozoitic, trophozoitic, and gametocytic forms.

When a mosquito bites a person with malaria, it ingests red blood cells infected with Plasmodium "gametocytes," the pathogen's sexual stage. Inside the gut of the mosquito, the male and female gametocytes mature and mate to form "zygotes." The products of the zygote mitosis, "ookinetes" migrate through the peritrophic matrix lining the mosquito stomach and form into "oocysts". The oocysts enlarge as the nucleus divides, and eventually rupture to release thousands of motile "sporozoites," which migrate to the salivary glands of the mosquito.

If the mosquito then bites another person, the sporozoites are incidentally injected from the mosquito's mouth into the person's blood. Within 30 minutes, the sporozoites travel to the person's liver, enter the liver's hepatocyte cells, and transform into "merozoites" that grow, multiply, and infect more cells.

During the time when the parasites are in the liver, the newly infected person does not yet felt sick. After some time—anywhere from eight days to several months—the parasites leave the liver and enter red blood cells where, as "trophozoites," they grow and multiply.

The infected red blood cells eventually burst, freeing merozoites to attack other red blood cells and releasing Plasmodium toxins into the blood, making the person feel sick. If at this point another mosquito bites this sick individual, it will ingest the tiny parasites, and after a week or more, the mosquito can infect another person.

A New Hope

One major breakthrough in the fight against malaria has been an effort, detailed in the current issue of the journal Nature, to complete the genome sequence of Plasmodium falciparum. There are four types of human malaria—Plasmodium vivax, P. malariae, P. ovale and P. falciparum—and Plasmodium falciparum is one of the most common and the single most deadly type of malaria pathogen.

The sequencing was difficult because many stretches of the genome of Plasmodium falciparum are rich in A–T pairs of DNA base, which account for 82 percent of the genome sequence. This makes Plasmodium DNA unstable, causing it to fall apart when the scientists tried to work with it. Add to that the sheer number of bases that had to be sequenced, and it is no wonder some in the field thought it could never be done. One scientist who led the sequencing effort likened it to tearing up six Bibles, scattering them over a football field, and piecing the pages together again.

The DNA pages of this particular pathogenic book were taken from a Dutch schoolgirl who contracted malaria after spending one night with her parents aboard a barge near Schiphol Airport, Amsterdam in July, 1979. Scientists believe she was bitten by a mosquito that came in on a plane from Africa. The samples taken from this girl's blood over 20 years ago have proven indispensable because scientists were able to trick the tiny parasites into going through their lifecycle in the laboratory.

Now finished, this major, six-year, $17.9-million effort involving 185 researchers from the United States, United Kingdom, and Australia was complemented by two other large genome-sequencing efforts. Also reported in this week's Nature is the complete genome sequence of the rodent parasite Plasmodium yoelii yoelii.

In the current issue of the journal Science, another international consortium of researchers reports the genomic sequence of the Anopheles gambiae mosquito, the primary malaria animal "vector," which is responsible for transmitting Plasmodium falciparum in up to 90 percent of malaria cases worldwide.

Two different groups from The Scripps Research Institute also have reports in the latest issues of Science and Nature that detail additional work related to this project. The combined research of the hundreds of scientists who have been involved in this effort should result in the identification of new targets for the development of drugs, which may be more effective than those under development today.

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Scientists have known for more than 100 years that malaria is caused by a microscopic parasite transmitted by a pest common to wet, marshy places—the mosquito Anopheles gambiae. Illustration courtesy of the Mandeville Special Collections Library.