Dave O'Brochta places his fingers on a net that covers the top of a bucket containing hundreds of Anopheles stephensi, a mosquito responsible for transmitting malaria. The mosquitoes slowly gather at the net and begin to probe his fingers. They are vectors for one of the world's most deadly diseases, and O'Brochta would like to turn them into supervectors. In collaboration with Sanaria, a Rockville, Md., vaccine company, O'Brochta is seeking ways to make the mosquitoes hypersusceptible to malaria infection. The company is designing a vaccine using malaria parasites harvested from the mosquitoes, and the more parasites that infect a mosquito, the better. (Click here for a feature on the impact of global health initiatives.) "This is increasing their production facility," O'Brochta says.
The project is one of a few O'Brochta oversees in the insect transformation laboratory at the University of Maryland's Biotechnology Institute (UMBI) in Shady Grove. The lab, a core facility for insect genetics, consists of a few insectaries (warm rooms with buckets of mosquitoes), some micromanipulators to inject insect embryos, several computers, a microscope room, and a whole lot of empty benches.
The empty benches are designed to be used by visiting scientists taking advantage of the new space, built in 2006. It was designed as a first-of-its-kind facility, where scientists from any institution or company could use the infrastructure and pay for services to genetically engineer an insect to their liking. While such commercially based facilities and companies exist for mice or fruit fly genetics, O'Brochta says there aren't any for insects other than Drosophila.
Without O'Brochta's lab and its commercial footing, Sanaria would have had to collaborate with an academic, noncommercial lab, a process that Peter Billingsly, the scientific director of Sanaria, says isn't as straightforward as contracting with the transformation lab. "We would have had to go through a much more elaborate grant application, because they may have needed to employ more people or boost their facilities a little bit," Billingsly says.
The basic technique the lab uses is transformation technology – injecting larvae with transposable elements that will insert genes and markers randomly into the insects' genomes. "There are a handful of labs that are big enough and have enough resources to do this," O'Brochta says. For smaller labs, the investment to start up transformation experiments on non-drosophilid insects can take many months and cost tens of thousands of dollars. Instead, for about $2,000, O'Brochta can have transformed larvae shipped to a PI within about three months.
In the fall of 2007, Mike Riehle at the University of Arizona sent O'Brochta a request to transform Aedes aegypti, the mosquito that transmits yellow fever, with a PTEN homolog, which essentially shuts down insulin signaling. Riehle is interested in designing shorter-lived mosquitoes, but first he is doing the opposite: inhibiting insulin to extend their lifespans. As O'Brochta shows me, the project has been a success. In a small plastic dish placed under a microscope, a handful of A. aegypti flit about. Under fluorescent light their eyes glow red, proof that a transposable element with a Ds-red marker and the PTEN homolog successfully invaded their genomes.
Riehle decided to use the transformation lab for this project because he didn't have enough hands in his own lab. "We do a lot of transformations in our lab," says Riehle, "but when they sent me results of how many embryos they tried to transform, it's jaw-dropping." Compared to Riehle's 15% survival rate for injected embryos, Robert Harrell, the transformation lab's manager (and the best larval surgeon in the world, according to O'Brochta), got a survival rate of 60%. "They are the experts," Riehle says.
O'Brochta's goal is to get enough interest from others like Riehle and Sanaria to at least make the lab financially sustainable, and to fill those empty lab benches with visiting scientists. "I'm not sure the facility is going to be a profit-making enterprise," says O'Brochta. Currently the UMBI subsidizes the lab, which consists of O'Brochta, Harrell, and three other technicians. The lab is far from sustaining itself, he says, and he was unable to estimate when it might have enough clients to pay for itself. "We'll assess it in three to five years," he says.
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