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Let it snow: field-testing malaria-refractory strains by inundation

January 24, 2011 - 18:54 -- Mark Benedict

In July of 2010, the Mike Riehle lab reported that they had created a transgenic strain of Anopheles stephensi that was refractory to malaria (first author Corby-Harris (here and here). However, as they noted, there is no way to spread the transgene into wild populations thus making this an important laboratory finding waiting for an undeveloped drive mechanism. I’ll argue that this provides an opportunity rather than a hurdle. How? Read on.

Alan Robinson and I (here) and Luke Alphey (here) have argued that developing transgenic applications for mosquito control should be done incrementally, beginning with simple self-limiting approaches: transgenic mosquitoes that are sexually sterile are a safe place to start, and they offer the possibility of a positive effect on public health. This anticipated beginning has occurred as the first releases of “sterile” Aedes aegypti that have been performed in Grand Cayman and those that are planned for Malaysia.

I don’t want to get carried away by an early small success, but if GM mosquitoes find acceptance, we will likely arrive at a time when spreading resistance genes (often called pathogen refractoriness) in wild populations is possible. First some background that shaped the current thinking.

The common assumption is that resistance effectors or the transgene insertion per se will have a negative fitness. Even if it were introduced into a wild population, selection would quickly eliminate it. So what is needed to make this strategy work is an engine; a drive mechanism which would increase the frequency of the resistance effector in spite of the fitness cost that it confers. Assuming that either the engine or the effector could break down by mutation at some frequency, it will be prudent - and essential - to field-test the two components individually in a test not confounded by the characteristics of the other. (This reasoning and the approach can equally apply to a vector of viruses such as Aedes aegypti.)

Let’s return now to the resistant strain of Corby-Harris et al. that blossomed from the mystical Arizona desert. I propose that this gene could – even should - be tested in natural populations by inundation. The activity would consist of releasing fertile resistant males in large numbers into (semi-) isolated natural populations. “What’s the point? This will have no lasting effect unless releases continue. The gene will simply disappear.” Thank you. That is exactly the point.

It is self-limiting, but it provides several highly informative pieces of information about the effector that would influence whether it should ever be paired with a drive mechanism. The outcomes of such as release include:

  1. The increase in the frequency of the transgene in wild populations would demonstrate the practical capacity to produce and release males and the degree to which they mate competitively. (It also should prove informative regarding the population size and perhaps, mosquito dispersal capacity, but neither of these requires GM mosquitoes.)
  2. If the releases continued sufficiently long, it could provide an indication of the likelihood of parasites developing resistance to the specific effector.
  3. Again, depending on the duration and level of the releases, it would provide measurable, though not permanent, reductions in malaria transmission.
  4. When releases ended, a definitive measure of the fitness cost of carrying the gene could be obtained by the rate of its declining frequency.
  5. The first real parameterization of a transgene mutation rate in wild mosquito populations would be obtained. (Natural mutation rates could reasonably be applied to a stable transgene, but this has not been determined experimentally.)

While this sounds like an experiment of little lasting benefit to the populace that participates, it must be viewed as an essential, first step in developing more valuable, driven effectors that would in fact have a durable effect.

Perhaps readers can suggest an alternative to this general approach for determining the potential of effectors when challenged with real parasites, in wild genetic backgrounds and in the presence of humans. I cannot.

Are more laboratory studies of the Corby-Harris stock warranted before a field test is performed? Certainly. But unless red lights appear, preparation for inundation experiments could proceed.

The risks of such a trial are negligible: the benefits are great. The malaria relief and encouragement that would result from a positive trial would extend from research labs to at-risk populations that have often been assured that novel interventions were on the way.