Driving Forward

(January 19th, 2017) Super-Mendelian inheritance is one of those terms that recently stopped being science fiction. It turned previous legislation into actual fact and made us wonder how to rule its science. This technology called “gene drivers” faced a ban from the United Nations last December. 

Having grown up in Costa Rica, I remember when the most beautiful girl in the class stop showing up in primary school. A mosquito (Aedes aegypti) had decided to infect her with the dengue virus. She recovered in a couple of weeks just to reject, again, my invitation to be my girlfriend. Our teacher made clear to everyone that her chances of surviving a second infection would be low because the fever would become haemorrhagic. Twenty years later, when I heard of gene drive mosquitoes that render the wild populations sterile, I was happy about erasing those annoying critters from the planet. On a second thought, who knows whether the mosquitoes are key to some unnoticed ecological process. On a third thought, I didn’t know whether “gene drives” work. Last December, however, Andrea Crisanti and Tony Nolan at Imperial College London proved the principle beyond doubt, sterilising a laboratory population of Anopheles gambiae, the vector of Malaria.

The gene drive technology is based upon the fact that diploid organisms carry two copies of each chromosome. In nature, the genes on one chromosome don’t attack the genes on the other chromosome. However, in organisms carrying gene drivers, one genetically-modified chromosome contains the information to destroy a sequence on its homologue chromosome.

Assume we have two chromosomes, each containing the gene A, but with slightly different sequences, or alleles, called A* and A+. The A+ chromosome is engineered to produce a CRIPSR endonuclease and its guiding RNA, which targets the A* gene on the other chromosome. Once produced, the RNA-guided endonuclease seeks the sequence of A* and cuts it. This double strand break is sensed by the DNA repair system, which is forced to use the sequence of the intact A+ as a template, to repair the broken A* chromosome. In the end, both chromosomes will carry the A+ allele. In Mendelian genetics, A+ and A* would have had 50% chance to be handed down to the offspring. But in the super-Mendelian genetics of gene drives, A+ has a 100% chance of being inherited, while A* is wiped out.

Crisanti and Nolan went further, designing a system to exterminate A. gambiae. In their mosquitoes, the CRISPR gene driver system is only expressed in the germ lines of both sexes, thanks to the vasa2 promoter. Three genes that are required for female fertility (AGAP005958, AGAP011377 and AGAP007280) can be targeted. Thus, when a female mates with a male bearing this gene driver system, their offspring will be composed of sterile females and more males carrying the gene drive. After a couple of generations, fertile females disappear.

Since this method has the potential to drive an entire species into extinction (something we humans never do, ask smallpox!), a coalition of environmental activists asked the United Nations Convention on Biodiversity (CDB) for a general ban on the gene drive technology. The UN, however, rejected the moratorium, saving a couple of PhD theses. The “Decision Adopted by the Conference of the Parties to the Convention on Biological Diversity” only talks about advising the governments to take a “precautionary approach”. Scientists themselves have expressed concern, arguing that, theoretically, resistant alleles can and most likely will evolve. Indeed, even Crisanti and Nolan showed this to be the case, experimentally.

Whether the resistant alleles could make things worse, or whether the extinction of a species might leave on open niche for another to rise, is currently unknown. Gene drivers should, in any case, be a reversible process. We should keep some wild type populations of mosquitoes, just in case we need to re-introduce them. Furthermore, mosquitoes released in Gambia are not going to show their passports before entering Senegal. However, modelling a field release of gene drive mosquitoes with “explicit spatial and temporal dynamics”, Eckhoff et al. concluded last week that the gene drive approach “provides a tool for malaria elimination unlike anything presently available”.

Hence, the worst thing that could happen, would be to stop the research.


Photo: www.publicdomainpictures.net/George Hodan

Last Changes: 02.14.2017