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alaria has confounded some of the originally described more than 100 years ago Even before the whole genome had been
best minds of the past century. A and were given names based on morphology, sequenced, new drug targets were being
hundred years after the discovery such as merozoite, trophozoite and gameto- identified from searches of the partially
that mosquitoes transmit Plasmodium falci- cyte (in humans), and zygote, ookinete and assembled sequence data for unique genes8.
parum, the major parasite that causes human sporozoite (in mosquitoes). One of the most But the total sequence will provide a more
malaria, we still do not know enough about curious features of the human stages is the complete picture of the parasite’s inner
the disease to defeat it permanently. But the human immune response — there is much workings and the chance to identify vulnera-
papers on pages 498–542 of this issue1–7, immune activity, but this does not control ble aspects. So just what have we learnt about
describing the complete genome sequence of the infection effectively, nor afford protec- the parasite’s biology from this package of
P. falciparum, may eventually lead to new tion against future infections. papers, which comprises its genome
drugs and vaccines, and will certainly be an Despite massive efforts to eradicate the sequence1,4–6; a comparison of its genome
invaluable guide to future research. These disease in the 1950s and early 1960s, more with that of a rodent malaria parasite, P.
papers are a testament to the success of a six- people are infected with malaria in Africa yoelii yoelii 2; and two proteomics studies of
year project undertaken by an international today than at any other time in history. Over the proteins expressed at different stages in
consortium of labs and funding agencies. 500 million people are infected with the the parasite’s life cycle3,7? Where are the
disease worldwide, and one-quarter of the potential weaknesses? And what have we
Why genome sequencing? population is at risk of infection. More than a discovered about the parasite’s means of
First, a bit of background. The malaria para- million children die of malaria each year, evading the human immune response?
site leads a complicated life (Fig. 1), existing mostly in Africa. And those individuals who
mainly inside liver cells and red blood cells in survive suffer a combination of anaemia and Metabolism
its human host and, when residing in mos- immune suppression that leaves them vulner- One notable feature of the parasite’s
quitoes (notably Anopheles gambiae), being able to other fatal illnesses. Alarmingly, drug genome1 is the apparent absence of genes for
associated with the insect’s gut and salivary resistance in the parasite is now widespread. proteins that, in other species, are key to
glands. It undergoes several transformations These stark facts emphasize the need to metabolism and the energetics of mitochon-
along the way. The stages of its life cycle were find new treatments for the disease and new dria — cellular powerhouses, which produce
the energy-storing molecule ATP. For exam-
a Sporozoites b ple, the consortium found no predicted
genes for two protein components of ATP
synthase, a mitochondrial ATP-producing
Salivary enzyme. (At present, many of the genes are
glands
Liver only ‘predicted’: they have been identified by
gene-searching algorithms, but have not
yet been confirmed as bona fide genes.)
Similarly, there are apparently no genes
Sporozoites for components of a conventional NADH
Merozoites
dehydrogenase complex, another key mito-
Red blood
cells chondrial enzyme. Perhaps P. falciparum
Oocyst
Gut generates and stores energy by using novel
proteins or mechanisms — potential drug
targets. That the mitochondria are active, at
Ookinete
Trophozoite least in sporozoites and gametocytes, seems
Zygote likely, given that the proteomics analyses3,7
detected fragments of enzymes involved in
Gametocytes Gametes
some typical mitochondrial processes,
including the tricarboxylic-acid cycle and
oxidative phosphorylation.
Figure 1 Life cycle of the parasite Plasmodium falciparum. a, When a parasite-infected mosquito feeds Also interesting is the number of predict-
on a human, it injects the parasites in their sporozoite form. These travel to the liver, where they ed genes — some 10% — that encode
develop through several stages, finally producing merozoites which invade and multiply, via the proteins associated with the apicoplast1. This
trophozoite stage, in red blood cells. Eventually, up to 10% of all red cells become infected. (Clinical essential cellular compartment is known to
features of malaria, including fever and chills, anaemia and cerebral malaria, are all associated with be important for the biosynthesis of fatty
infected red blood cells, and most current drugs target this stage of the life cycle.) The merozoites in a acids and isoprenoids, components of many
subset of infected red blood cells then develop into gametocytes. b, When another mosquito bites the membrane proteins, and for iron metab-
infected human, it takes up blood containing gametocytes, which develop into male and female olism. But analysis of these genes should
reproductive cells (gametes). These fuse in the insect’s gut to form a zygote. The zygote in turn develops reveal other possible functions, and so new
into the ookinete, which crosses the wall of the gut and forms a sporozoite-filled oocyst. When the drug targets. The genome sequence also
oocyst bursts, the sporozoites move to the mosquito’s salivary glands, and the process begins again. identifies the molecules within the apicoplast
NATURE | VOL 419 | 3 OCTOBER 2002 | www.nature.com/nature 495
T
he papers that appear in this issue, Plasmodium is taken up by mosquitoes in
transcription. Perhaps this is a general describing the genome of the human blood meals drawn from infected humans
feature of the parasite — another potential malaria parasite Plasmodium falcipar- (see the life-cycle diagram on page 495). The
drug target. um, are published simultaneously with others parasite then undergoes several developmen-
In addition, one of the proteomics stud- in Science tackling the genome of the mosqui- tal stages, and crosses two mosquito cell layers
ies3 reveals groups of genes whose regulation to Anopheles gambiae. The connection is that enclose the insect’s midgut and salivary
appears to be coordinated. Some simultane- obvious: the parasite requires a mosquito to glands. Ultimately, Plasmodium is passed on
ously expressed genes are clustered in the complete its complex life cycle and for trans- when the mosquito bites a new human host,
genome; comparison of these genes and their mission from one host to another. These two about two weeks after ingesting the first
flanking sequences may provide further species are respectively the major parasite infected blood meal. For more than a century,
insight into how they are regulated. causing malaria and the major vector. an objective of malaria control programmes
496 NATURE | VOL 419 | 3 OCTOBER 2002 | www.nature.com/nature