One of the main lessons scientists learned in the pesticide wars of the last century was that both mosquitoes and malaria are highly adaptive. Therefore, despite the importance of Jacobs-Lorena's achievement, everyone involved realizes it's not enough. "In order to ensure success," notes James, the UC-Irvine geneticist, "we need to build a transgenic mosquito that kills malarial parasites in a number of different ways. We need to make sure we can stay a few steps ahead of evolution."

Due to malaria's 10-day gestation period, scientists can attack the parasite at different places. Jacobs-Lorena blocked the receptor that the parasite binds to inside the insect's mid-gut. James is working on the inverse. Over the past six years, he has figured out ways to block a molecule produced by the parasite that allows it to bind to the insect's salivary glands. In that time, he has reduced malaria levels in the mosquito by 99 percent and feels it likely that he can get the level down to zero within the next year.

A very different approach is being undertaken by Alexander Raikhel at the University of California at Riverside. Raikhel has figured out how to boost a mosquito's immune system. A mosquito's system naturally produces certain proteins in the presence of foreign bacteria. But since malaria is a parasite, not a bacteria, it doesn't normally have to deal with those proteins. Raikhel has figured out a way to trick the mosquito into producing them during the period of time when the malaria sits inside the insect's gut. The result is a mosquito with a turbo-charged immune system that turns on every time there's a chance the mosquito can get malaria -- thus killing the disease before it has the chance to spread.

This work is the only such enterprise in existence. Nowhere else are scientists fiddling with genetics in an attempt to stop the spread of disease. But exciting as finding a way to kill animal malaria in the laboratory seems, it's only the beginning of the process. The next few steps are about finding a way to make this work in the jungle.

Even the first of these steps, building a transgenic insect that exists on a par with normal mosquitoes, was thought to be a Herculean task, but in work that has just been completed (and has yet to be published) Jacobs-Lorena says that his transgenic mosquitoes have the same life span and produce the same number of offspring as normal mosquitoes. "This means," says Lorena, "that in laboratory conditions there's no fitness cost to building mosquitoes with an immunity to malaria."

But the transgenic mosquito must be stronger than regular mosquitoes. "For us to really control the disease, we still have to find a way to make our transgenic insects have more offspring than wild mosquitoes," says Jacobs-Lorena. Much of this work is being done by Atkinson and James; their computer modeling will be followed by lab studies followed by, ultimately, field studies. "We still need to understand how transposable elements move through a mosquito population," says Atkinson, "and we need to know how to make this more efficient."

What these scientists are looking for is a non-Mendelian mechanism for driving these genes into a wild population: They want something quicker than typical insect birth rates. The ideas being explored include using a jumping gene or attaching the malaria-blocking gene to a virus or bacterium that has the ability to rapidly travel through a wild population. Until this research occurs, no one can say how long it will take to actually eradicate the disease.

Simultaneous to this work, some of the teams are undertaking the switch from mosquitoes that carry animal malaria to mosquitoes that carry human malaria -- a feat not as easy as it sounds. Not only are the mosquitoes that carry human malaria much harder to breed in captivity, but there are also differences between the animal models and the human models. The same gene that blocks malaria in Jacobs-Lorena's mice does not work in humans, although Jacobs-Lorena has reported in another study soon to be published that he believes he's found another gene to accomplish the task.

In experimenting with human malaria, the risks associated with the enterprise become greater. There's no way to build transgenics with a human form of malaria immunity without first breeding insects with the human form of malaria. So now there's a level 3 bio-containment laboratory on the UC-Riverside campus complete with multiple airlocks, electronic passkeys, and drainage systems that dump waste water, not directly into the sewer system, but into a heating chamber that cranks up high enough to boil off anything untoward.

There are sound reasons for the building's Fort Knox approach. One concern is that some of the mosquitoes might escape and people would get malaria. Even more worrisome is a problem addressed in the fall of 2002, in a report published by the National Academy of Sciences titled "Animal Biotechnology: Science-Based Concerns." It is primarily a study of the dangers of genetic modification and its possible impact on the environment. Starting with what we already know, that jumping genes got their name because of their ability to hop around a genome and hop from species to species, the report examines existing laboratory conditions and the amount of work currently done in these labs and then, using a low-to-high scale, ranks the chances that existing transgenic animals could escape, become feral, interbreed with wild populations and potentially produce something that we've never seen before. Across the board, insects rated in the high category.

And even if the Riverside containment lab does its job, and neither of those things occur, the progression of this work to the next stage brings a whole host of other ecological concerns. We know very little about how mosquitoes live in the wild. We don't completely understand how they breed -- meaning everything from how they select certain mates to why they choose to lay their eggs in one puddle of water rather than another. We lack understanding of how seasons affect population size or how wide a territory certain populations inhabit or, critically, how and why genes travel through given populations. Thus we don't yet know all the dangers involved in tinkering with this balance. "This is a high-risk venture with a high-yield outcome," says Collins.

To combat the risk, Collins and James and others have been advocating for just this type of basic research. Back in the mid-'90s, inspired by their anti-malaria transgenic work, insect ecologists at UC-Davis and elsewhere made long strides into understanding everything from mosquito breeding patterns to gene flow. Already, in Kenya, there exists a giant screened-in greenhouse, complete with mud huts and breeding puddles, dubbed the "malariasphere." There scientists are studying population dynamics and transmission rates. Even so, Collins quickly points out that whatever we learn from the malariasphere is a drop in the ocean of what we need to know.

The reasons for our need to know are more than a little frightening. Mosquito-borne ailments are among the most devastating and successful diseases on earth. The chemical paradigm of the last century produced a disease immune to our drugs and an insect immune to our pesticides. What if genetically modified mosquitoes result in yet another boost for disease-carrying insects?

"The chances that we're going to end up making a Frankenstein mosquito are pretty remote," says Collins -- but even he agrees that the possibility exists.

Even if our transgenics don't end up vectoring a super-malaria, James points out there are other things to worry about: "If by making a mosquito unable to transmit malaria, will it suddenly become possible for that insect to vector another disease that, as of yet, is not transmitted by mosquitoes? A disease like AIDS?"

Will we assuage all these fears before releasing transgenic mosquitoes? "There's no way to know exactly what will happen in 10 thousand generations of mosquitoes," says Atkinson. But we do know the threat of mosquito-vectored disease is growing more serious every year, and as that threat rises so does the possibility of a new page in history.

In 77 A.D., Pliny the Elder published "Natural History," his rather imaginative 37-volume attempt to catalog the entire contents of the world. From him, we learn that the artichoke is one of the earth's great monstrosities; that dog-headed people who communicate by barking exist; that on islands off the coast of Germany live a tribe of people whose ears are so large they cover their entire body; and that arsenic, sulfur, caustic soda and olive oil are used to protect crops against pestilence. That last bit of information might seem wan compared to other elements in Pliny's mythic compendium, but it is our first written record of insecticides. And now, two thousand years later, the next time someone sets out to catalog the entire contents of the world, there will be a new entry in that great list: a mosquito that lives a dual life as the direct descendent of two of Pliny's described lineages: both a fantastical creature and a pesticide.

Recent Stories