Figures & data
Figure 1. Synthetic approach to making anti-parasite effector genes. A synthetic approach to making an anti-parasite effector gene starts with a simple model of a gene (A) comprising two parts. The control region contains cis-acting DNA that regulates when during development, where in the vector insect, and how much of a product is made. Constitutive and regulated endogenous mosquito genes with sex-, stage- and tissue-specific expression profiles have been used for the control regions (Table ). The effector region is the expressed portion of the gene that kills or disables the parasite. This may result from a direct action such as a single-chain antibody that binds the parasite or toxin that kills it, or an indirect action that deprives the parasite of an essential host factor, blocks an important ligand or elevates a systemic immune response (Table ). (B) Control regions can be selected to deliver effector molecules to specific compartments (midgut, hemolymph [open circulatory system] and salivary glands) in which specific parasite stages are found.
Notes: Malaria parasites enter the mosquito midgut (shaded red) as gametes following an infectious blood meal. Male and female gametes fuse to form zygotes that mature into motile ookinetes. Ookinetes penetrate the midgut epithelium and form an oocyst in which thousands of sporozoites develop. Sporozoites emerge from the oocyst and migrate through the hemolymph to the salivary glands (shaded yellow) prior to transmission to a new human host.
![Figure 1. Synthetic approach to making anti-parasite effector genes. A synthetic approach to making an anti-parasite effector gene starts with a simple model of a gene (A) comprising two parts. The control region contains cis-acting DNA that regulates when during development, where in the vector insect, and how much of a product is made. Constitutive and regulated endogenous mosquito genes with sex-, stage- and tissue-specific expression profiles have been used for the control regions (Table 2). The effector region is the expressed portion of the gene that kills or disables the parasite. This may result from a direct action such as a single-chain antibody that binds the parasite or toxin that kills it, or an indirect action that deprives the parasite of an essential host factor, blocks an important ligand or elevates a systemic immune response (Table 1). (B) Control regions can be selected to deliver effector molecules to specific compartments (midgut, hemolymph [open circulatory system] and salivary glands) in which specific parasite stages are found.](/cms/asset/a8c7d333-746a-4691-b5ee-e31fa8831a00/ypgh_a_1427192_f0001_oc.gif)
Table 1. Antimalarial effector genes and targets.
Table 2. Anopheline mosquito cis-acting DNA elements for expressing effector molecules.
Figure 2. Genotypic and phenotypic outcomes of gene-drive systems.
Notes: Genes-drive systems impact the outcome of inheritance ratios in heterozygous mosquitoes. The scheme shown here is neutral to the drive mechanism (CRISPR/Cas9, transposable elements, underdominance, etc.). A wild type mosquito (yellow) is fully competent (C) to transmits malaria parasites and has the genotype C/C. A mosquito carrying a dominant gene (blue) that makes it incompetent (I) to transmit malaria parasites is designated I/I. During Mendelian inheritance (left panels), a cross between the I/I and C/C mosquitoes produces heterozygous progeny, I/C. A test cross of the heterozygotes to the fully competent parental strain, C/C, results in the equal (50%) recovery of progeny in each class, I/C and C/C. In contrast, a similar experiment with a perfect gene-drive system (right panels) results in the recovery of progeny all of which are incompetent, I/I.
Figure 3. Pathways for development of population modification technologies.
Notes: Population modification technologies will progress from the laboratory-based work of Discovery to Development before they can be certified for Delivery. Discovery laboratories may interact through one or more pathways to bring the technologies to countries with different scientific, regulatory and social capabilities. Independent disease-endemic countries (DECs) need little or no assistance from discovery laboratories as published information is sufficient for them to make their own mosquito strains and test them. Some DECS will need help making DNA constructs (DNA-only) but all subsequent work (transgenesis, phase trials) [Citation11] will take place in-country. Other DECs will need discovery laboratory assistance with making both the DNA constructs and strains to be tested (DNA/Strain).
