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The parasite genome ways of preventing it. The genome project

described in this issue1–7 was conceived with
Biological revelations these goals in mind. With the wealth of infor-
mation now available at the click of a mouse,
Dyann F. Wirth malaria researchers have an unprecedented
opportunity to find genes that are potentially
The genome of the malaria parasite was sequenced with the aim of unique to, or at least substantially different
learning more about how the parasite works, and with the hope that in, P. falciparum compared with other
this would reveal potential drug targets. Has that hope been realized? species; such genes may make good drug
targets, with less risk of side effects.

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
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
dehydrogenase complex, another key mito-
Red blood
cells chondrial enzyme. Perhaps P. falciparum
Gut generates and stores energy by using novel
proteins or mechanisms — potential drug
targets. That the mitochondria are active, at
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 | 495

© 2002 Nature Publishing Group

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that are the targets of several existing drugs9. Immune evasion The complete picture
The complex life cycle of P. falciparum Arguably the most striking features of the P. One of the most exciting aspects of this huge
means that the parasite has had to adapt to falciparum genome are the regions near the undertaking is that it can be related to other
several different environments. So it is also ends of each chromosome1. This is where work. We now have the genome of the
intriguing that, compared with the genome of families of genes that encode surface mosquito A. gambiae15, together with draft
the free-living budding yeast, the parasite proteins, such as the var genes, are found. sequences of the human genome16,17, and so
genome1 encodes a limited number of pre- These proteins, or antigens, can sometimes can get a better handle on the interactions
dicted transporter proteins for the active be recognized by and thus stimulate the among three species that have long been
uptake of nutrients from the environment. In human immune system. But they have a evolving together. It is well known that cer-
fact, entire classes of transporters seem to be great capacity for change, which occurs part- tain variations in human genes are associat-
missing. It may be that several genes in this ly through the exchange of material between ed with a reduced susceptibility to malaria,
class have been overlooked because they are chromosome ends. As the genome sequence and analysis of different human populations
made up of many small coding regions, which shows, the very ends of the chromosomes — will no doubt reveal more on this. A close
can be missed by gene-prediction algorithms. the telomeres — have a complex arrange- look at the mosquito genome should pro-
But, taken at face value, this surprising finding ment of sequences that may facilitate such vide similar insights. Study of the parasite
implies that adequate amounts of nutrients exchange (as described in ref. 13) and there- genome will reveal much about how P. falci-
recognized by the transporters must be by lead to immune evasion. parum interacts with its host and carrier, and
present at all stages of the parasite life cycle, so The general structure of the chromosome more about the genes involved in parasite
that there is no selective advantage in having ends is similar to that in the rodent parasite P. recognition by the human immune system.
many transporters with differing substrate yoelii yoelii 2. But, surprisingly, the genes that Decoding the information in these genomes,
specificities. Alternatively, the parasite may encode the variant surface antigens in P. falci- and translating it into effective remedies, is
use previously identified pores or channels parum are not found in P. yoelii yoelii, which both a challenge and an opportunity for the
to acquire nutrients10,11. has a different family of variant genes, origi- scientific community. ■
nally described in a less virulent human para- Dyann F. Wirth is in the Department of
Regulating protein levels site, P. vivax14. This is interesting, because it Immunology and Infectious Disease,
During its life cycle, P. falciparum undergoes suggests that P. yoelii yoelii, which is often Harvard School of Public Health, 665 Huntington
several developmental changes. One of the used as a model of P. falciparum, is in some Avenue, Boston, Massachusetts 02115-6021, USA.
most dramatic is sexual differentiation and respects more similar to P. vivax. It is tempt- e-mail:
the formation of gametes, male and female ing to speculate that, despite their dissimilar 1. Gardner, M. J. et al. Nature 419, 498–511 (2002).
reproductive cells. The proteomics studies3,7 sequences, the genes at the ends of the P. falci- 2. Carlton, J. M. et al. Nature 419, 512–519 (2002).
3. Florens, L. et al. Nature 419, 520–526 (2002).
of these stages have coincidentally shed light parum and P. yoelii yoelii chromosomes have 4. Hall, N. et al. Nature 419, 527–531 (2002).
on a fundamental question: how does the similar functions. But that remains to be seen. 5. Gardner, M. J. et al. Nature 419, 531–534 (2002).
parasite regulate the levels of its proteins? Finally, research on the P. falciparum var 6. Hyman, R. W. et al. Nature 419, 534–537 (2002).
The genome1 encodes relatively few predict- genes has focused on their role in enabling 7. Lasonder, E. et al. Nature 419, 537–542 (2002).
8. Jomaa, H. et al. Science 285, 1573–1576 (1999).
ed proteins that control the transcription of infected red blood cells to stick to small blood 9. Waller, R. F. et al. Proc. Natl Acad. Sci. USA 95, 12352–12357
genes into messenger RNAs (the first step in vessels in the brain. This feature is associated (1998).
making a protein). Moreover, there seem to with the fatal form of the disease, cerebral 10. Desai, S. A., Bezrukov, S. M. & Zimmerberg, J. Nature 406,
1001–1005 (2000).
be few transcriptional regulatory elements malaria. So it is interesting that one of the
11. Kirk, K. Nature 406, 949–951 (2000).
in the genome — or at least, there are few proteomics analyses3 reveals that the peptides 12. Dechering, K. J. et al. Mol. Cell. Biol. 19, 967–978 (1999).
elements that are known from other organ- derived from many of the var genes occur in 13. Freitas-Junior, L. H. et al. Nature 407, 1018–1022 (2000).
isms. Yet the proteomics analyses and previ- sporozoites, which are produced in mosqui- 14. del Portillo, H. A. et al. Nature 410, 839–842 (2001).
15. Holt, R. A. et al. Science 298, 129–149 (2002).
ous studies show that protein abundance is toes and invade the human liver during the 16. International Human Genome Sequencing Consortium
tightly regulated. initial infection. These results point to possi- Nature 409, 860–921 (2001).
The proteomics studies also show that ble alternative functions for vargene products. 17. Venter, J. C. et al. Science 291, 1304–1351 (2001).
proteins involved in processing mRNAs
and in protein synthesis (translation) are
expressed at higher levels in gametocytes, The mosquito genome
particularly female gametocytes, than in
other stages. Interestingly, proteins that are
present in early zygotes — which are pro- The post-genomic era opens
duced from gametocytes — seem to be Ennio De Gregorio and Bruno Lemaitre
absent in gametocytes, although the mRNAs
encoding these proteins are abundantly The mosquito Anopheles gambiae is the main agent in the transmission of
present. All of this is consistent with the human malaria. Its genome sequence will in time help to devise control
proposal12 that the regulation of protein strategies, but will be a more immediate boon for insect biologists.
levels is controlled through mRNA process-
ing and translation, rather than by gene

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 |

© 2002 Nature Publishing Group