Seldom does so much news appear so suddenly that it grabs me by the ears and says, “You MUST write a blog. Now!” Following are the highlights of recent publications that reflect the maturing potential for genetic control to affect malaria and dengue transmission. If you’re interested in a quick summary of recent news and views, here it is.
Those trained in genetics and molecular biology of mosquitoes feel they simply must (and sometimes even do) do something useful with their technological contributions. I often ponder the words of the late Chris Curtis (1985) who wrote that “…in the late 1960s and early 1970s this [desire to do something useful] led us to start work on some intellectually delightful but impractical schemes.” I too can submerge myself in such schemes, but fortunately, there are a large number of critics who will usually throw one a life-preserver of practicality.
Even today, with more sophisticated and nuanced abilities to modify mosquito phenotypes, I often feel we are trying to pound the square peg of genetic control of mosquitoes into a round hole of malaria transmission. Or worse, we are trying to convince ourselves that the malaria transmission hole actually is square. In either case, self-delusion awaits to grab us by the ankles like a troll under the bridge
Enough reflection on whether any of the following actually matters in the real world. Several pieces of news have been erupting recently and a blog is long overdue. (No I have not forgotten the promised part II mentioned in my last blog. Hang in there.) Where to start when each one could merit a blog on its own?
(Please note that I define genetic control of vectors as “Dissemination, by mating or inheritance, of factors that reduce harm.” As you’ll see, that includes dissemination of bacteria that could be vertically transmitted, not only inheritance of a transgene.)
Here we go, in no particular order.
Lindsey S. Garver, Ana C. Bahia, Suchismita Das, Jayme A. Souza-Neto, Jessica Shiao, Yuemei Dong, George Dimopoulos
The take home is that the Imd immune pathway can be activated by RNAi silencing of caspar. The team showed high levels of reductions (not absolute elimination) in the number of P. falciparum oocysts in Anopheles gambiae (see Fig. 4 for impact). This is a significant step forward in understanding the immune response and developing tools that have the potential to be used to make truly malaria-resistant mosquitoes. (IMO, a truly malaria-resistant mosquito does not develop sporozoites at a rate that can maintain transmission.) Is this is an effector for genetic control of malaria transmission? That is another question. Would the levels of reduction actually influence transmission? And how to drive a transgene (if one is developed based on this) into populations? See my blog ("Let it snow") for initial test ideas.
Alison T. Isaacs, Nijole Jasinskiene, Mikhail Tretiakov, Isabelle Thiery, Agnès Zettor, Catherine Bourgouin, Anthony A. James
Transient expression (above) is an entirely valid step in developing anti-malarial effectors, but I have a fondness for demonstrations of anti-Plasmodium effects using as this is an effect that could be deployed. That’s exactly what has been accomplished in this report.
The Tony James-led group developed transgenic lines of An. stephensi expressing single-chain antibodies against P. falciparum. Importantly, they demonstrated that in many mosquitoes, no sporozoites developed, leading the team to “…propose that the m1C3/m2A10 dual transgene can be used in the further development of a population replacement strategy to control the transmission of the human pathogen, P. falciparum, by An. stephensi.” (I’d be sticking the transgene into An. gambiae to see if the effect is duplicated. An. stephensi is an easier mosquito to work with than An. gambiae, but no longer not so much that similar experiments cannot be conducted in gambiae.) Demonstrating reductions in a pre-sporozoite stage is great. But if you are interested in effects on transmission, sporozoite effects are essential. They’ve done it here. Nice.
Oxitec has teamed with Moscamed, an old hand at sterile insect technique against medflies and the University of Sao Paolo to conduct a program against Aedes aegypti near Juazeiro, Brazil using their bi-sex lethal RIDL strain. The project has been an overall success with good reductions (claim of ~85% or more) in the target population in spite of the proximity of wild populations that would likely reduce the effect. The team has now opened an expanded production facility on the Moscamed grounds. It will be the first real “mosquito factory” in existence since the 1970s.
This project is one of the largest for Oxitec, and perhaps more importantly, it’s a more convincing public health partnership than previous programs because more extensive regulatory oversight and clear public engagement were conducted. That’s not to say that what has been done elsewhere was deficient, but it has been widely criticized. I’ve heard less criticism of this effort, but as the project expands, it’s sure to come.
The technology has been welcomed by the residents where the program is being conducted. It would be a shame if outside interference eventually denied the residents a technology that they desire. The open reception of the Brazil releases contrast with the attitude toward RIDL technology in Florida, USA, where well-organized environmentalists are resisting efforts to suppress Aedes aegypti using RIDL. No feared environmental catastrophe has occurred yet, but of course like all apocalyptic predictions, it’s best not to claim when The End will come, only that it surely will.
One final comment on the Brazil releases: The team should make post-release monitoring a major part of their activities. Among other things to monitor will be distant dispersal, effects on co-inhabitants of larval sites and effects on predators. It would be good to commission these studies by an independent authority to ensure that they are respected. However, epidemiological effects will be hard to assess this early.
A bit off the beaten track for The New Yorker perhaps, but Specter takes an in-depth and comprehensive look at the potential for RIDL technology to affect dengue transmission. He covers the history, technology, people (developers and environmentalists included) that are involved in implementing – and criticizing - the technology. This is a must-read that is refreshingly agenda-free, and in sobering contrast to this blog, elegantly written.
Wang S, Ghosh AK, Bongio N, Stebbings KA, Lampe DJ, Jacobs-Lorena M.
Just when you glance away from the activities of a lab, they score a big one. Years ago, Marcello’s lab diverted away from transgenic approaches to affect vector competence and toward symbionts. While I personally thought that it was too early to be discouraged about germline transformation’s potential, Marcello’s decision is paying off and proving that a different approach was a good call.
In this paper, they use a naturally occurring gut symbiont, Pantoea agglomerans, to deliver anti-malaria peptides against P. falciparum and berghei. They observed large reductions in oocyst numbers with some of the effectors. Unlike the paper above, there was no report of the most significant indicator of the potential for reducing transmission - sporozoite numbers – but this is a major advance toward an anti-malarial technology that one can envision as being field-deployable in the near-term. Marcello and his collaborators are clearly headed in a fruitful direction.
(One note: maybe I’m picky, but I’m uneasy with undefined use of terms like “efficient” and summaries of effect such as “up to.” I am also puzzled whether the bacteria proliferate in the crop – the primary destination for sugar meals, the delivery system that was used for the bacteria. I am also curious as to whether they expect an anti-plasmodial peptide to have off-target effects in other organisms that will come in contact with the bacteria.)
In summary, this has been a busy period for genetic control with significant advances on several fronts. Given the diversity of reports, it appears genetic control is not only a square peg, but a triangle a pentagon…
Curtis, C. (1985). Genetic control of insect pests: growth industry or lead balloon? Biological journal of the Linnean Society, 26(4), 359–374.