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August 20, 2016 is World Mosquito Day. A special post by NAS member Anthony A. James of the University of California, Irvine.
Happy World Mosquito Day! I am guessing that many of you are now asking “Are you joking?” No, it’s true. World Mosquito Day was first established by Sir Ronald Ross in 1897, when he proposed an annual observance of his discovery that mosquitoes were involved in malaria transmission. Sir Ronald was not a shy man, but in fairness to him, this was a truly noteworthy finding and led to many innovative and effective ways to control the disease in many parts of the world.
So now you are thinking “Well, if this was such a big deal, why is malaria still a problem? I hear that over 45% of the world’s population is at risk of contracting malaria, and current estimates are that there were over one-quarter billion cases and ~600,000 deaths in 2014, more than 90% of these in Africa.” Fair enough (and you’ve heard a lot!), but the answer is complicated. There are many circumstances where geographical, economic or political realities make it such that effective malaria vector control tools never get applied. Furthermore, there are many circumstances where the tools are applied but do not work. Insecticide-treated bed nets and indoor residual spraying do not work on outdoor, daytime feeding mosquitoes. Most tragically are those places where these tools used to work but now no longer do. This is mostly a result of insecticide resistance, but natural disasters and public health infrastructure decay also contribute. So many of us believe that along with the better use of existing tools, we need new ways to prevent transmission of this disease.
“So what are you doing about it?” Well, malaria in humans is a disease caused by protozoan parasites transmitted by infected female Anopheles mosquitoes. Males don’t bite and are not involved directly in the transmission dynamics and not all Anopheles mosquitoes transmit human malaria. As we used to say “It’s genetic”. Even within species that do transmit parasites, it is possible to select for variants that do not. This resistance to parasites in many cases results from the action of one or a small number of genes. My colleagues and I thought that if we could just get these genes into all of the mosquitoes, game over, no more malaria. But it was not that easy, so we decided that we would make genes that confer resistance.
“How did you do that?” We built synthetic genes that when turned on in the mosquito inhibit the parasites. We envisioned a simple model of a gene with two parts, a control region that tells the gene ‘when, where and how much’ to turn on, and an effector region, which when turned on in the right time and place would block the parasites. We took the control sequences from natural mosquito genes that were turned on at the right time and place where malaria parasites would be.
There are a lot of species of malaria parasites: the ones that infect humans do not infect mice and the ones that infect mice do not infect humans. A while ago some of our vaccine friends took human parasites and put them into mice. The mice laughed them off (do mice laugh?), and mounted immune responses that dispatched the parasites. We were able to take the genes encoding the components of the mouse immune responses that allowed them to fight off the human parasites and engineer them so that they would function in the mosquito. And it worked! We could knock out the parasites in the mosquitoes.
So now you are thinking “Cute trick, but how are you going to get them out into the wild mosquitoes?” We had hoped to couple the genes we made to what is called a gene-drive system by which genes could be spread quickly through populations. We worked a long time unsuccessfully on a number of different mechanisms for gene drive and were about ready to call it quits when something good came along.
“OK, OK! What was it?” Friends of ours, Valentino Gantz and Ethan Bier at the University of California, San Diego, devised a way to use the CRISPR/Cas9 system to effect gene drive in the famous vinegar fly, Drosophila melanogaster. They e-mailed me their results and asked if I was interested. Are mosquitoes annoying? We were able to combine their system with ours in such a way that they are inherited by ~99.5% of the progeny in crosses of the transgenic to wild-type mosquitoes in the laboratory.
“What’s next?” Well, this first version is a prototype and we need to build a better one for phase trials before it can be considered for field applications, an approach called ‘population alteration’. While it alone will not solve the malaria problem everywhere, it has the chance to help a lot. We believe that long-term, cost-effective and sustainable malaria elimination requires strategies resilient to immigration of parasite-infected mosquitoes and people. Wild mosquitoes invading a region populated by altered mosquitoes acquire parasite-resistance genes by mating with the local insects. Persons with parasites moving into that region cannot infect the resident mosquitoes, and therefore do not serve as a reservoir for infecting other people. Population alteration also exploits the ability of male mosquitoes to find females. Release of a population alteration strain should eliminate pathogen-carrying mosquitoes in carefully selected endemic areas. As elimination efforts progress, the strategy takes on a larger role as a mainstay of the prevention of a reintroduction phase. As elimination is achieved, the stably altered released mosquitoes allow resources to be moved to other regions with the confidence that the cleared area will remain disease-free. Thus, population alteration offers a real chance to achieve sustainable elimination and contribute to the malaria eradication agenda. None of this will be possible without the consent and cooperation of the people living in the malaria-endemic areas and proper regulatory oversight.
“Enough already! I just want to know what’s involved in the celebration. Do we wear green, drink tequila, exchange gifts and cards?” It is customary to donate to one (or more) of the non-profit organizations that work to alleviate this miserable disease. You can donate money for bed nets, research, drugs or any aspect that interests you. I want to keep my friends, so I won’t name a specific organization. I urge you to go online and read about the ones that are there. Do it, you’ll feel good about yourself and you will make a difference!
Anthony A. James
Department of Microbiology and Molecular Genetics
and Molecular Biology and Biochemistry
University of California, Irvine
You can read more about Dr. James’ work at his website.