Genetically Modified Mosquitoes

An excellent example of synergy and a true paradigm shift is the development of genetic control strategies that essentially move away from mosquito population reduction to population replacement with insects no longer capable of transmitting pathogens. The initial synergy originates from studies that succeeded in germline transformation of Drosophila, in the early 1980s (Spradling and Rubin 1982). It wasn't until 1991, when a now historical meeting was held in Tucson (Anonymous 1991) that the strategy of incapacitating disease vectors through genetic transformation was coined. The thinking here was certainly transformational: rather than killing mosquitoes, let's replace them with ones that are harmless. It is not surprising, therefore, that this leap in thinking generated enormous interest from both the scientific and funding communities (Fig. 3). The strategic space that was opened up left those in search for incremental improvements of population reduction strategies far behind. Both the National Institutes of Health (NIH) and the World Health Organization (TDR) were captivated by the idea and devoted major resources (both financial and HR wise) to this new endeavor. Although genetic control strategies had been developed against mosquitoes decades before (Curtis 2006), these all focused mostly on population control. Interest in these had waned, because of technical hurdles but surely also because of the problems related to reinvasion and inability to eliminate local populations. The idea then to drive genes that confer refractoriness through populations resolved these issues, thereby increasing its appeal.

Fig. 3 The GM (genetically modified) mosquito endeavor, which opened up strategic space in vector control and resulted in high appeal to both the scientific and funding community because of its radical deviation from classical approaches

Strategy:

population replacement

Insecticide

Strategy:

population replacement

Insecticide

L Strategy: population reduction

Incremental

Transformational

L Strategy: population reduction

Incremental

Transformational

The synergy resulted in remarkable progress within a decade. Successful stable germline transformation of An. stephensi was accomplished in 2000 (Catteruccia et al. 2000). Just two years later the first transgenic mosquito with much reduced ability to transmit rodent malaria was created (Ito et al. 2002). The value creation of these successes has proven more difficult. To date, no efficient drive mechanism is available, no effector molecules to target human malarias (in particular

P. falciparum) have been identified, and GM mosquitoes suffer from fitness losses (Marrelli et al. 2006) although this may be compensated for when mosquitoes are actually being challenged with parasites (Marrelli et al. 2007). Much bigger hurdles are to be expected when moving towards field implementation, in the absence of proof-of-principle under near natural conditions. Although these experiments are now underway (Clayton 2006), it remains uncertain how end-users will view this approach. Not only are ethical, legal and social issues the most neglected aspects of this approach so far, also within the scientific community major scepticism abounds with nearly two-thirds of those asked "will the transgenic mosquito ever fly to control malaria" either answer "no" or "have no opinion" (Knols et al. 2007). It is imperative, therefore, to not only have the operational power to define the future of GM mosquito research, but also have criteria power. These criteria are often defined outside the scientific community yet may have major implications on the ability to further the approach towards full field evaluation. In other words, synergy is more powerful with due consideration of the potential for value creation.

It is interesting to compare this with the development of malaria vaccines. In spite of decades of research, the value creation of this approach has never been questioned because of the grand successes that have been accomplished with vaccination (e.g. smallpox eradication). Without any synergy, all vaccines are after all based on active immunization, the value of the approach remains incredibly strong, even when it is acknowledged that a commercial vaccine may be a decade away at best. What the GM approach lacks is value creation; evidence that in operational as well as biological terms there is a good chance of success.

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