Windbichler:Research

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We now have the ability to precisely alter and replace the DNA of living cells - the targeted engineering of genomes. Today the ever growing tool-set enables genetic modifications ranging from the alteration of single base pairs to the generation of entirely synthetic chromosomes. Reprogrammable enzymes such as the modular TALE or the RNA-guided CRISPR/Cas endonucleases have been used to modify a plethora of genes in model and non-model organisms.

Such nucleases are also being developed to modify and correct genes patient cells; the beginning of genome engineering as therapy. Other novel tools such as synthetic programmable transcriptional activators as well as transcriptional repressors or epigenetic modifiers can be used to rewire genetic pathways and change the state of cells in new ways. Form here one can move to create new genetic functions, new gene networks, new organs and even new species.
Such a synthetically-oriented approach to life and biological species that goes beyond the natural is a prominent and recurring theme in the history of biology over the last century. It ranges from Luther Burbank’s famous “New Creations” in 1893 to Hugo de Vries claim that evolution had to become an experimental science with the help of which he wished to create new species rather than crossing existing ones.This power is beginning to transform genetics and genomics and will ultimately transform agriculture and medicine and society. Our research is based on the exploitation of some these new tools and possibilities; not only for growing the toolkit itself and to move forward with the construction of ever more complex human-designed biological systems but also for applying this new powers to tackle real problems.



Genetic engineering of populations

One application we work is the control of insect pests or insect vectors of disease. One of greatest challenges science has ever faced is that by 2050 the world’s population will increase to over 9 billion people. Insect pests cause huge losses to agricultural production and a changing climate, the spread of invasive species following in its wake as well as the rise of insecticide resistance is predicted to increase the burden of insects on agricultural production and on human health with half the world's population now at risk from vector-borne disease. According to the WHO, vector-borne diseases are responsible for close to 1 million deaths each year and insecticide-resistant mosquitoes now inhabit more than 60 countries.

New tools for the control of insect pests and disease vectors can save and improve the lives of millions in disease endemic countries.

How can genome engineering help to control an insect vector population? We work on various avenues for genetic control, a form of biological control that has the potential to replace more indiscriminate methods of pest control and thus reduce ecosystem degradation.
To this end we have been developing ways to genetically engineer pest populations using a technology called "gene drive". This strategy of "population genetic engineering" can be used to render vector populations incapable of transmitting disease or, by directly attacking essential genes, reducing such populations in size. In addition we have also been developing methods to bias the reproductive sex ratio of populations towards males. We developed the first synthetic sex-ratio distortion trait in the malaria mosquito using an endonuclease to cleave a repetitive DNA sequence found solely on the X-chromosome.

By restricting endonuclease activity to spermatogenesis, X-bearing sperm were selectively destroyed and eggs were predominantly fertilised by Y-bearing sperm destined to produce males. Because X-shredding, unlike female-killing, operates meiotically no significant reduction in male fertility is incurred and because it operates independently of the endogenous sex-determination cascade it is applicable, at least in principle, to any heterogametic species. Genetic linkage of the sex distorter transgene with the Y-chromosome or its mobilization by “gene drive” would generate a self-perpetuating intervention as such a genetic trait could rapidly invade and eliminate a natural vector populations even if initially seeded at a very low rate.
The power of these concepts we are realizing have been theoretically recognized more than 50 years ago by the British biologist W.D. Hamilton who concluded: “The implied method of biological control is in theory very powerful, since the mere seeding of a population with a few prepared males could cause its extermination.”