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June 12, 2008

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OXFORD, England -- In a hot and humid laboratory, an army of • See a sample reprint in PDF
genetically altered mosquitoes zip around translucent plastic format.
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boxes, feasting on horse blood. Bred by a start-up called Oxitec
Ltd., the bugs are on a mission to kill off their brethren with the
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Sex may be lethal to mosquitoes if British researchers have their
regular males
way. WSJ's Guatam Naik reports on experiments with a sexually in the battle for females and eventually cause
transmitted gene that would make mosquito offspring sterile. the population to collapse.

A plan, still in its early stages, has been hatched to unleash the newly armed insects 6,500
miles away in Malaysia. Authorities have been desperate to tame the growing scourge of
dengue fever, a largely urban disease transmitted via a striped mosquito known as Aedes
aegypti. In what would be the first release of an insect genetically programmed to kill other
insects, scientists may release millions of genetically modified mosquitoes to crash the wild
population of aegypti, and, they hope, stop dengue in its tracks.

But that's a big hope. Dengue, whose incidence has soared in recent decades, has been
nicknamed "break-bone fever"; the flu-like illness causes severe joint and muscle pains. A
rarer form kills. The World Health Organization estimates that there are 50 million dengue
infections each year and as many as 2.5 billion people are at risk.

The project is causing a buzz of worry. "What's the consequence on the ecosystem if you wipe
out an entire species?" says Gurmit Singh, chairman of the nonprofit Centre for Environment,

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Technology and Development in Malaysia. "You may solve one problem but create another."

In April, local newspapers reported that the Malaysian government would soon test-release the
bugs on an island near Kuala Lumpur, the capital. After a public outcry, the government
insisted the move wasn't imminent.

As a form of pest control, sterile male insects

have been unleashed plenty of times before.
The U.S. used the method to rid itself of a
flesh-eating fly called the screw worm by
1966. In Zanzibar, sterile males vanquished
the tsetse fly in the mid-1990s. In both cases,
the bugs were sterilized with old-fashioned
radiation. The technique has never worked too
well on mosquitoes.

Fiddling with an insect's genetic makeup is a

more radical idea. Researchers in India and
France have created silkworms that were Oxitec
The World Health Organization estimates there are 50 million
genetically modified to defend against a dengue infections a year.
deadly virus that usually kills them. There are
similar early-stage efforts to make GM mosquitoes that don't transmit malaria.

In the U.S., scientists irradiate and release millions of pink bollworms in order to control
populations of the cotton pest. Last summer, the U.S. Department of Agriculture went one step
further. Of the 2.4 million creatures released in southern Arizona, half had a genetic
modification: an extra piece of DNA that gave them red fluorescent markings on their body,
making them easier to identify under a microscope.

Created by Britain's Oxitec, the transgenic bollworms -- they're really caterpillars that become
moths -- "behave quite like the untransformed sterile strain," says Greg Simmons, a USDA
entomologist.

Oxitec was spun off from Oxford University in 2002 and is still partly owned by that
institution. At its labs on a recent afternoon, a researcher used a thin glass needle to inject
liquid DNA into a mosquito embryo. The hope was that the foreign DNA would lodge in a
suitable part of the embryo genome.

It's a laborious process. "We need to do a few thousand injections to get just one success," says
Luke Alphey, co-founder and chief scientist of Oxitec. When it works, the inserted gene
produces fluorescent proteins in the larvae that hatch.

The transgenic critters have a more important property: Their offspring are programmed to die
in the larval stage if they aren't fed tetracycline. The antibiotic is part of their feed in the lab.
Without access to tetracycline in the wild, any larvae born there can't survive.

Only female mosquitoes bite humans and animals on whom

they feed. (Males don't bite; they sup on plant juices and sugary
saps.) Upon mating, they require proteins from a blood meal to
develop their eggs. Consequently, when female mosquitoes
smell a person nearby, they are more inclined to mate.

"Humans emit more than 300 odors -- that's how mosquitoes

track you down," says Bart Knols, entomologist at Wageningen

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University & Research Center in the Netherlands, who is

familiar with Oxitec's research. (Dr. Knols is big on bad smells: In 1996, he published a paper
showing that the female malaria mosquito was as attracted to the stink of Limburger cheese as
to the odor of human feet.)

Malaysian scientists recently tested Oxitec's bugs in a specially built four-room house.
Research volunteers took turns sitting behind a protective mesh screen, acting as olfactory
stimuli for 10 female mosquitoes that had been released into the rooms. Also buzzing around
were 10 males from the wild and 10 of Oxitec's special male bugs. The big question: Would
the females go for the genetically engineered sterile males or the wild ones?

After eight hours, the females were separated and allowed to dine on the blood of rats. They
were then placed in special containers where they could lay their eggs. If a particular larva that
hatched had the fluorescent marker on its body, it was clear that female had mated with an
Oxitec mosquito.

After a few dozen such experiments, the results indicated that the females showed no
preference for the regular males over their genetically modified rivals. The next possible step
is a controlled experiment to measure the technique's effectiveness in the wild.

There are safety concerns. Geneticists, for example, fret about horizontal gene transfer,
whereby the alien DNA from the Oxitec mosquitoes would somehow jump into microbes or
other organisms, with unforeseen consequences, such as harming another species. And while
the chances are low that random mutations will restore fertility to sterile males, the probability
goes up when millions of genetically modified mosquitoes mate in the wild.

Scientists "presume these accidents won't happen, but there's no evidence they won't," says Joe
Cummins, professor emeritus of genetics at Canada's University of Western Ontario, who
recently cowrote an article that criticized the safety aspects of Malaysia's mosquito project.

Oxitec's Mr. Alphey is less concerned. "You have to look at this on a case-by-case basis to
understand what DNA was inserted and how it was inserted" into a transgenic insect" he says.
"We don't think our strain poses a significant risk."

Write to Gautam Naik at gautam.naik@wsj.com1

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