GM chickens could pave way for H5N1-resistant flocks if tall political, technical and economic hurdles can be overcome. 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 January 14, 2011 in Science. 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 Laurence 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. 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 cage mates.
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. 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.
January 24, 2010
Original web page at Nature