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Editorial: Effective malaria management has bugged scientists for decade Now we may have an effective answer

Full article by Andrew Ross.

  • Summary
  • Introduction
  • References

Developed by scientists across the world, including those in the UK, the genome editing procedure, termed the clustered regularly interspaced short palindromic repeats (Crispr) system type 2, has been employed to alter the genetic structure of anopheles stephensi mosquitos writing in genes coding for antibodies that target and kill the malaria parasite (plasmodium falciparum), that typically infects and resides within the mosquito, to be passed on to humans.

The aim of this gene modification technique employed by James and co-workers is to produce a phenomenon called a gene drive, whereby these genetically modified mosquitos breed with the existing population and cause a genetic shift to produce a species of mosquito with antimalarial properties. Very recent research conducted by Professor Anthony James (University of California, Irvine) has shown that these antimalarial genes as passed on to offspring 99.5% of the time, evidenced by the presence of a marker gene giving the modified strains red fluorescent eyes. James, a leading expert in the field of gene drive, focused on the nopholes stephensi species, which is responsible for about 10% of the cases of malaria in India.

When I came across a recent article in the guardian newspaper about a new solution to the ever persistent problem of malaria I expected to be reading about the emerging pipeline of clever antimalarial drugs that are being developed to tackle a disease that still claims the lives of 400,000 people each year. However it seems that the scientific communities sustained interest in gene therapy has again promised the hope of an emerging therapy that may revolutionize our approach to this disease. But instead of focusing on people, this new therapy aims to alter the genetic make up of the parasite vector; the mosquito.
The Process
Developed by scientists across the world, including those in the UK, the genome editing procedure, termed the clustered regularly interspaced short palindromic repeats (Crispr) system type 2, has been employed to alter the genetic structure of anopheles stephensi mosquitos writing in genes coding for antibodies that target and kill the malaria parasite (plasmodium falciparum), that typically infects and resides within the mosquito, to be passed on to humans
The Crispr – Cas 9 system was initially discovered in bacteria as a means of protection against invading viral pathogens. There are two main components to the system; a guide RNA and the Cas – 9 endonuclease. In a bacterial system, the guide RNA binds to the invading viral DNA and allows for targeted Cas-9 mediated cleavage at particular sites in the pathogen genome. This technique has been manipulated for scientific use by altering the guide RNA’s structure so that researchers can design a complementary sequence (known as the spacer) to target specific genes. Once the targeted gene has undergone double a double strand break at the desired point, natural DNA repair mechanisms are employed to resolve the defect. Typically this occurs via non homologous end joining (NHEJ), a highly efficient process that results in small nucleotide insertion or deletions (indels), causing mutations (frameshifts, deletions, insertions) that ultimately silence the targeted gene. Cells can also employ an additional repair mechanism, termed homologous end joining. In this process, a template sequence to be inserted into the broken DNA needs to be provided, typically as a single DNA strand or double stranded plasmid template. Through this repair mechanism, a gene can be edited by the incorporation of this additional template sequence at the point of the strand break, an outcome being employed in malaria research. A final use of this technique involves the inactivation of Cas-9’s endonuclease activity such that it binds to targeted sites but does not cause strand breaks. By doing this at sites such as the gene promoter region, and with the potential pairing of Cas 9 with gene co activators/repressors, gene expression can be modulated using this system.
Gene Drive
The aim of this gene modification technique employed by James and co-workers is to produce a phenomenon called a gene drive, whereby these genetically modified mosquitos breed with the existing population and cause a genetic shift to produce a species of mosquito with antimalarial properties. Very recent research conducted by Professor Anthony James (University of California, Irvine) has shown that these antimalarial genes as passed on to offspring 99.5% of the time, evidenced by the presence of a marker gene giving the modified strains red fluorescent eyes. James, a leading expert in the field of gene drive, focused on the nopholes stephensi species, which is responsible for about 10% of the cases of malaria in India.
The Problems
As with all types of gene therapy, gene modification and genetic drive has the potential for serious and unpredictable consequences, in this case from an ecological perspective. As a result, a number of safeguards have been put in place to protect laboratory research using genetically modified species. Leaders of the field have recently signed a call for increased safety over gene driven research to ensure that modified species do not make their way out of the laboratory. To progress further, the researchers need to test their insects in small arenas and field cages before open field tests can be conducted.
With the increasing resistance to insecticides and anti malarial drugs, gene modification and gene drive have the potential to significantly contribute to researcher’s efforts to control and perhaps eradicate malaria. Furthermore, the effects of gene modification can be extended to diseases other than malaria and offers an exciting prospect in the research into a multitude of diseases.

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