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The year 2012 marks the tenth anniversary of the announcement of the genome sequence of the human malaria parasite Plasmodium falciparum and that of its mosquito vector Anopheles. The genome sequences were a result of the Plasmodium falciparum Genome Project. This book covers in detail the biology of malaria parasites and the mosquitoes that transmit the disease, how the Genome Projects came into being, the people who created them, and the cadre of scientists who are attempting to see the promise of the Projects realized. The promise was: a more complete understanding of the genes of the parasite (and its vector) would provide a rational basis for the development of antimalarial drugs and vaccines, allow a better understanding of the regulation of the complex life cycle in the red blood and liver cells of the human, identify the genes the parasite uses to thwart the host immune response and the ways in which the parasite evades cure by drug treatments, as well as leading to more effective measures of control transmission. The hope was that cracking the genetic code of Plasmodium and Anopheles would reveal the biochemical Achilles heel of the parasite and its vector, leading to the development of novel drugs and better methods of control, and by finding the targets of protective immunity could result in the manufacture of effective vaccines.

Synthetic peptides patterned on the amino acid sequences found in two exofacial regions of band 3 protein (residues 824-829 of loop 7 and residues 547-553 of loop 3) blocked, in a dose-dependent fashion, the in vitro adherence of Plasmodium falciparum-infected erythrocytes to C32 amelanotic melanoma cells. Intravenous infusion of these synthetic peptides into Aotus and Saimiri monkeys infected with sequestering isolates of P. falciparum resulted in the appearance of mature forms of the parasite in the peripheral circulation. The finding that the peptides were effective as adhesion blockers in the micromolar range suggests that cerebral malaria could be managed through antiadhesion therapy.

DNA is the stuff of which genes are made. DNA was discovered more than a century ago by an obscure Swiss physician, Friedrich Miescher (1844–1895) [162]. Shortly before completing his doctoral dissertation (1868), Miescher elected not to follow in his father's footsteps as a hospital physician and teacher of pathologic anatomy and instead pursued a career in physiological research. In part, it is believed, this was due to his partial deafness, the result of an earlier attack of typhus that certainly would have limited his abilities to use the stethoscope and perform percussion and auscultation [392]. He joined the laboratory of Felix Hoppe-Seyler (1825–1895) at the University of Tübingen, Germany, with the intention of studying what enables the cell to live and how cells are fashioned into tissues. Hoppe-Seyler, whose interests were in the chemistry of blood, was one of the first to crystallize hemoglobin and describe the interaction of oxygen with hemoglobin in the red blood cell. He was now turning his attention to a white blood cell, the lymphocyte, present in pus as well as blood. Hoppe-Seyler thought an understanding of the chemistry of the lymphocyte might lead to a better view of why pus was formed during infections. The collaboration was ideal: Miescher wanted to analyze the chemical composition of the cell and Hoppe-Seyler had the \"perfect\" cell for Miescher to analyze, the lymphocyte. Today a study of pus cells would be impractical inasmuch as infections are rare, but in 1869 when Miescher began his studies there were no antibiotics and antiseptic methods during surgery were non-existent, so human pus was readily available from the surgical wards of many hospitals [392]. In addition, he could take advantage of the newly invented clean, sterile, absorbent cotton used for dressing pusfilled wounds [162]. Hoppe-Seyler encouraged young Miescher; however, he also cautioned that there was no method to study pus chemistry! Miescher learned by trial and error and after many failures finally succeeded when he extracted pus-laden bandages with a weakly alkaline solution; a highly viscous, snot-like material that was impossible to handle as it would not dissolve in water, acetic acid or sodium chloride was obtained. (In hindsight we now know that this occurred because the solution he used extracted high molecular weight DNA.) He asked himself, from where in the cell did this material come? Was it the nucleus, the membrane, the cytoplasm? Examining the pus cells under the microscope he observed that the alkaline solution caused the nucleus in the pus cell to swell and break open. This suggested that the nucleus was the source of this material and hence he named the substance \"nuclein.\" Using element analysis, one of the few chemical methods available at the time, he found the new substance to contain 14% nitrogen, 3% phosphorous, and 2% sulfur. This ratio of nitrogen to phosphorous was unique. Further, finding it to be resistant to digestion by pepsin (found in the stomach), he concluded the material could not be a protein. By August of 1869 Miescher reported that the same material was found not only in pus cells but also in other cells with nuclei such as yeast, kidney, liver and chicken and duck red blood cells. Miescher did not understand the importance of nuclein as the carrier of inheritance [392]. Indeed, he considered nuclein to be a storehouse of phosphorous for the cell and to the end of his life he rejected the idea that nuclein might have something to do with heredity…

In an article on 10 June 2010, Time magazine described a village in Uganda: \"Lake Kwania is more of a giant swamp: shallow, full of crocodiles and choked with lily, papyrus and hyacinth. The malaria parasite loves it here. Kwania's creeks…are perfect for a deadly…mosquito, Anopheles funestus, which feeds almost exclusively on humans, with an appetite to shame a vampire. The nearby town of Apac is packed with a living blood bank of people. The average funestus bites humans 190 times a night. And, the average resident is bitten tens of thousands of times a year, including 1,586 bites — four a day — that carry malaria\" [515] (http://www.time.com/time/specials/packages/article/0,28804,1995199_1995197,00.html?artId=1995199?contType=article?chn=specials)…

A celebration of the completion of the human genome sequence was held at the White House on 26 June 2000. The President at the time, Bill Clinton, said, \"it will have a real impact on all our lives — and even more, on the lives of our children. It will revolutionize the diagnosis, prevention and treatment, of most, if not all, human diseases.\" Those who, like Clinton, expected dramatic results overnight, would be disappointed in the years since the announcement. Among these would be Craig Venter who stood next to President Clinton and was involved in the race to sequence the human genome. In a Spiegel Online interview on 29 July 2010 he reflected on the Project: \"We have learned nothing from the genome and the medical benefits so far have been close to zero.\" In that same year Francis Collins, who shared with Venter in the completion of the human genome sequence, and was also alongside Clinton at the celebration, put it more gently: \"It is fair to say that the Human Genome Project has not directly affected the healthcare of most individuals\" [147]…

Malaria parasites need to live within a cell. This being so, getting inside is a must. As such, the molecular mechanisms of invasion may be the Achilles' heel to be exploited for the development of new therapies. Despite half a century of \"invasion research,\" however, a practical and effective means for interrupting the entry process into red blood cells has not been achieved. Nevertheless, the hope for novel interventions to prevent the parasites from getting inside remains and the Plasmodium genome sequences may aid in that regard…