Scientists create GM chickens that stop spread bird flu

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Transgenic chickens curb bird flu transmission

Genetic modification quells virus, but questions linger about use in developing

countries. by Virginia

Researchers have made genetically modified chickens that can't infect other

birds with bird flu. The H5N1 strain of influenza — which raged through

southeast Asia a decade ago and has killed hundreds of people to date — remains

a problem in some developing countries, where it is endemic.

The birds carry a genetic tweak that diverts an enzyme crucial for transmitting

the H5N1 strain. Although they die of the disease within days, the molecular

decoy somehow impedes the virus from infecting others. The findings are

published today in Science1.

The researchers say that although large-scale distribution of the genetically

modified (GM) birds will one day be feasible, their study is meant only to show

proof-of-concept of the technique.

" We have more ambitious objectives in terms of getting full flu resistance

before we would propose to put these chickens into true production, " says

ce Tiley, a molecular virologist at the University of Cambridge, UK, and

lead investigator for the study. His team is now working on further genetic

tweaks that would inhibit the virus in different ways. " It would be a bit like

combination drug therapy for HIV, " he says.

Other experts point out that even if the GM chickens carried full resistance to

influenza, there are political and economic hurdles to their widespread

commercial use — not least the public's aversion to GM food.

" It's the beginning of something which will require a certain number of years to

see whether it is accepted by the public, " says Ilaria Capua, head of virology

at the Experimental Animal Health Care Institute of Venice in Legnaro, Italy.

Path of destruction

H5N1 is endemic in at least five countries, and is particularly threatening in

Egypt and Indonesia, says Capua. So far, the virus has not been able to spread

from human to human, but some public health experts worry that eventually it

will adapt to do so.

In developed countries, H5N1 outbreaks are controlled by swiftly culling the

animals. In poor countries, however, there are lots of small farms, few health

regulations and long-held cultural practices involving birds. " In the developing

world, we cannot follow the slaughter strategy used in the developed world, "

says Arnold Monto, an epidemiologist at the University of Michigan School of

Public Health in Ann Arbor. " Politically they can't do it, and practically they

can't do it. "

Instead, developing countries try to control H5N1 by vaccinating birds. This

doesn't prevent them from silently acquiring mild forms of the disease and, if

not monitored well, transmitting it to healthy birds. What's more, flu viruses

mutate quickly and are famous for evading vaccines.

If made commercially available, the GM birds wouldn't have these issues. They

carry a genetic 'cassette' dubbed a short-hairpin RNA, which includes genetic

sequences that match up with an enzyme that influenza viruses use for

replication and packaging. These sequences can bind with the enzyme, somehow

stopping it from working with the virus.

The enzyme could mutate to evade this decoy, but if it did so it would no longer

be able to match up with its binding sites on the virus. So for the virus to

escape, it would need to simultaneously change its own genome and that of the

enzyme in eight different spots — a highly unlikely event.

The chickens were modified by a team led by Helen Sang, a geneticist at the

Roslin Institute of the University of Edinburgh, UK. The researchers modified

the chickens by injecting a lentivirus carrying the cassette into clusters of

cells on top of egg yolks. In some of the resulting chicks, the cassette

integrates into germ cells. These animals can be cross-bred to produce chickens

that carry the cassette in every cell.

The researchers infected decoy-carrying birds with H5N1 and housed them with

uninfected birds, some with the transgene and some without. Most of the birds

that received the primary infection died, but didn't pass on the flu to any of

their uninfected cagemates.

The researchers found that the amount of virus present in the infected GM birds

was not significantly different from that in non-transgenic controls.

" It must be something above and beyond the effect on replication that's having

this effect, " says Tiley. It could be, for example, that the hairpin disrupts

the packaging of the virus, preventing it from being taken up normally in the

next animal.

Don't count your chickens

Sang says that using their methods, it costs approximately £50,000 (US$79,000)

to produce " a small number of stable transgenic birds you can characterize and

breed from " . She and Tiley argue that getting similar transgenic birds into

global production would be possible because there are only a handful of

companies providing purebred chicken lines.

But this approach would not be feasible in poorer countries. " This will only

become affordable for the people who are well off, " says Marc Van Ranst, a

virologist at the Dutch-speaking Catholic University of Leuven in Belgium.

The technique may become most useful not for preventing the spread of H5N1, but

for using similar cassettes to create resistance to other common poultry

diseases.

Tiley's study was partially funded by Cobb-Vantress, a major international

chicken-breeding company. Cobb-Vantress told Nature they have no plans to

continue funding this work.

" All the companies are fairly sensitive to public perceptions, " says Karel

Schat, a virologist and immunologist at Cornell University in Ithaca, New York.

Schat is a paid consultant for another company that is also funding research on

using transgenes for disease resistance. " Scientists are excited. But it may

well be that people at the higher level of the companies are trying to be a

little bit more careful. "

References

Lyall, J. , et al. Science 331, 223-226 (2011).

http://www.nature.com/news/2011/110113/full/news.2011.16.html