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Genetic control via population replacement: where do transgenics stand?

November 30, 2012 - 16:43 -- Mark Benedict

Two blogs ago (here), I assessed the progress of population suppression by sterile males accomplished using either transgenic or conventional approaches. I promised then to compare methods of genetic control using either a “conventional” approach vs. a transgenic one in a future blog. Fortunately, I had the good sense to promise “what” but not both “what and when”, but here I go forward with that second effort. First some back-story.

Back in 1991 when many of you were being pushed around in strollers (“prams” for my British English readers) a formative meeting was held in Tucson, Arizona. The meeting was titled “Prospects for Malaria Control by Genetic Manipulation of its Vectors.” (BTW a great place for meetings as the air is fresh, dry and the scenery is dramatic.) The event was sponsored by the WHO and a critically strategic funder of nascent molecular sciences in mosquitoes – the John D. and Catherine T. MacArthur Foundation. The meeting was convened amidst an air of excitement about the advent of transgenic technology in Drosophila melanogaster: “Rubin and Spradling” and “Spradling and Rubin” were on everybody’s lips. (Look it up. I can’t do all the work here ;-) Surely, P would function in mosquitoes and soon we would be creating refractory mosquitoes within months. (piggyBac? RIDL®? HEGs? URL? What?)

Notice the meeting was not called “Prospects for Malaria Control by Genetic Suppression of its Vectors.” The theme was clearly developing refractory mosquitoes and spreading the trait through natural populations. The means to spread the factor at that time was envisioned as a transposable element, an idea that is a bit out of vogue now, but, in spite of obvious problems, it was really the only good option at the time. “Anophelism without malaria” was the goal, and P elements were the vehicle. (This failure to anticipate where the field would go is also a testament to how poorly the "best minds" are able to foresee the future.)

We’re two decades down the line now and the MacArthur Foundation backing has gone over the horizon to be replaced by Gates, but the effort to develop refractory mosquitoes has pressed on.

I’ll admittedly do a bit of comparing apples (dengue) to oranges (malaria) here, but I previously blogged on the remarkable success of Wolbachia-infected Aedes aegypti to inhibit dengue infection.

Wolbachia contain both an effector to inhibit infection in the same package as the spread mechanism. This solves a problem that has plagued efforts to spread transgenic refractoriness. Think of the refractoriness as the wagon. It needs a horse to pull it into the population. Wolbachia does both.You can check their updates here and see that things still look good, but not without growing pains.

In contrast, those developing malaria refractory mosquitoes have struggled to get to the point where we have some promising anti-malaria effectors, some of which I’ve highlighted previously here and here. So it appears that for anti-malaria effectors, we are on the verge of having a cart that might be worth putting a horse in front of. (I’ve argued that a good first step is to inundate a population with such a mosquitoes here and I still believe that is the only reasonable first step.)

Transgenic approaches to refractoriness to malaria have not been as easy or as rapid to develop as expected, and a horse is still needed. Perhaps mosquito symbionts such as Asaia will pull the cart, but this remains to be seen.

The association of Wolbachia with Aedes aegypti surprised the developers by being more effective than expected. It has provided both a drive and effector that none predicted. Here’s hoping for some similar surprises for transgenic approaches.