Engineering in the Wild: Driving Genes into Populations to Stop Malaria

Engineering organisms in the lab is, well, hard work. Developing a yeast strain that produces a single chemical at high yield within the highly controlled lab environment can take years of work and millions of dollars.

By comparison, the challenges of engineering organisms in the wild, changing the genetic structures of populations outside the lab for our or other organisms' benefit, seem daunting.

While releasing drug-making yeast into the wild wouldn't be particularly useful, introducing malaria-resistant mosquitos into the wild could potentially save lives. The malaria parasite's lifecycle requires that it develop within the mosquito prior to transmission to humans. Malaria resistance in mosquitos is already documented, and selective breeding or directed genetic changes could enhance this characteristic.

But there are a lot of mosquitos out there. Releasing a handful, even a truck-full, of lab-grown malaria resistant mosquitos won't make a dent. What's needed is a tool to drive traits of interest through a wild population, in a way that is possible with a manageable initial population of lab-grown colonizers.

In the early 1990s, an odd genetic element was discovered in flour beetles that might fit the bill. Called Medea, both an acronym for "maternal-effect dominant embryonic arrest" and a reference to the filicidal mother from classical mythology, it contains a sinister combination of poison and antidote.

Like all maternal-effect genes, the Medea product is deposited by the mother into her eggs. But in this case, the mother deposits a poison into the embryo that ceases its development. That is, unless the embryo itself inherits a copy of Medea (from either the mother or the father), which contains an embryonically expressed antidote.

Medea is a selfish gene in the most extreme sense: "inherit me or die." Even though the Medea gene region has been mapped in flour beetles, we don't know what the poison and antidote encoded by the Medea system are, or how they work.

But the principle is simple enough that it can be reverse engineered, which a group from Caltech has done in the fruit fly Drosophila melanogaster.

As the poison, they used a microRNA that shuts off the developmentally crucial gene myd88. For the antidote, they used a compensatory copy of myd88 switched on during early embryo development.

Mother flies carrying this engineered adaption of Medea deposit the toxic microRNA into their eggs. If the resulting embryo did not inherit Medea, the microRNA cancels out a sufficient quantity of Myd88 protein to inhibit development. However, the offspring that do inherit Medea have enough Myd88 to get the job done, given their extra copy of Myd88 carried within Medea itself.

Since the poison and antidote are adjacent on the chromosome, they are very likely to be inherited together. And there's nothing unique about Drosophila here. Mosquitos have their own developmentally important genes that could be utilized in the same way.

This creates the possibility of putting a cargo gene (or genes) between the two components of a mosquito Medea, for instance a gene that confers malaria resistance. Post-introduction, the trait would spread through the population in an accelerated fashion because of Medea's direct interference in reproduction.

With parasite resistance to each generation of anti-malarial drugs a threat, perhaps biological (rather than chemical) control of the malaria parasite is the way forward to eradication.

Image credits:

Mosquito: James Gathany/CDC (via Wikimedia); Flour beetle: Peggy Greb/USDA ARS (via USDA ARS)

References:

1. Beeman, R. W., Friesen, K. S., & Denell, R. E. Maternal-Effect Selfish Genes in Flour Beetles. Science 256, 89-92 (1992).

2. Chen, C-H. et al. A Synthetic Maternal-Effect Selfish Genetic Element Drives Population Replacement in Drosophila. Science 316, 597-600 (2007).

3. Lorenzen, M. D. et al. The Maternal-Effect, Selfish Genetic Element Medea is Associated with a Composite Tc1 Transposon. PNAS 105, 10085-10089 (2008).