Monday, July 19, 2010

Gut check!

A new article in PLoS Pathogens by a collaborative group led by Michael Riehle at the University of Arizona shows some progress in a long-sought genetic approach to disease control. While the news is, as usual, far ahead of the reality, the approach is interesting and may hold real promise for eventually helping to control one of the scourges of humankind--malaria.

The path is indirect and complicated to explain--but clever. Basically humans, and insects like mosquitoes, use insulin-like signaling among cells for their development. Mosquitoes depend on this from their blood meal. Riehle and colleagues have engineered a mosquito that carries a genetic change that over-activates a molecule (called Akt) in the insulin gene cascade, in the mosquito's gut.

The investigators said that a homozygous transgenic mosquito--one with two copies of the over-expressed gene--is 100% resistant to infection by the parasite.

The mosquito's lifespan is shortened by the insulin-cascade modification, so that the parasite's necessary time spent in its gut is too short for the parasite to fully develop, hence it's not ready to survive in the bitten human's blood stream. Hence, no malaria!

The idea that people have had in mind is not new, but this is a new approach. It's to 'seed' malaria-affected areas with these genetically modified mosquitoes, so that they would replace the native mosquitoes. The latter would simply die out by being out-competed in a sped-up evolutionary sense. If that happens, the parasite would have no insect gut in which to hide. That's why there would be no malaria.

Unfortunately, the engineered mosquitoes have a shortened lifespan and would likely be quickly out-competed by the local mosquitoes. Thus, the investigators will have to try some other genetic modification to give them a competitive advantage over the native mosquitoes. So we're years away from this kind of miracle.

Insecticides and anti-malarial drugs have the expected problem that they lead to resistance in Nature. The race to control mosquitoes by poisoning them, or to kill the parasite in humans, faces this kind of evolutionary arms race problem. The investigators hope their genetic approach might be added to the weapons we have against malaria.

Of course, there is every reason to expect that the parasite or transgenic mosquitoes would also develop genetic changes that could lead to reconnecting the pathogenic life cycles. There are many kinds of mosquitoes that carry lots of different malaria parasites, each of them different and naturally variable. So Nature can be predicted to out-wit any single genetic strategy. However, if the approach can be 'automated' and sped up, technology could continue to develop new attacks as current ones become ineffective.

In a different approach, British investigators are attempting to develop transgenic strategies against Dengue fever, another major killer (A story can be heard on the July 16 Science in Action program on the BBC). Again the idea is to seed the wild mosquito population with flies that in this case carry a gene expressing a toxin. The gene is inherited but in the absence of an antidote (which is not present in the wild), the descendants will die. If the transgenic flies mate successfully enough, the local population will die out. And so will the disease.  And, in yet another transgenic strategy, researchers are developing a female mosquito that can't fly; they project that the release of these mosquitoes into the wild would reduce the mosquito population drastically within 6-9 months, and thus reduce the Dengue fever problem.

It's still early days, but these strategies have in common the idea of strong artificial selection targeting specific genetic pathways in pathogens. One can hope they'll work.

No comments: