Controlling a bird flu pandemic

Controlling bird flu Crystals of neuraminidase from an avian influenza virus, subtype N 9, isolated from a noddy tern nesting on North West Island on Australia’s Great Barrier Reef. The crystals are about 0.6 mm across and are colourless. The colours are due to the lights used to illuminate the crystals for photography

Dr Elspeth Garman - University of Oxford
Professor Graeme Laver FRS - Murrumbateman, Australia
Ms Sandra McEwen - Australian Science

'We just don't know if bird flu will become easily transmissible between humans', says Graeme Laver, 'but if it does, control by quarantine would be hopeless, no effective vaccine may exist and our only defense will be the anti viral drugs Relenza and Tamiflu'. The story of the development of Tamiflu is an unlikely tale of idyllic coral islands, swabs of birds' backsides and growing crystals on the Soviet space station Mir.

A variety of influenza type A viruses had been detected in birds in the first half of the 20th century but as they were almost always found in domestic birds it was thought they originated from humans. Graeme set out to challenge this theory by isolating influenza viruses in wild birds. In the idyllic setting of an uninhabited coral cay off the coast of Australia, he set about taking samples from wild sea birds. In what Graeme describes as a eureka moment he discovered antibodies to the influenza virus, finally the influenza type A virus was isolated from one bird's throat swab. 'These birds were completely isolated from humans', explains Graeme. 'So it suggested that the natural hosts of influenza type A might be wild aquatic birds and not humans'. The research stepped up a gear when a colleague, Rob Webster, told Graeme he was swabbing the wrong end of the bird. 'Influenza viruses replicate in the bird's gut not in the lungs', says Graeme. 'So the bird's backside or cloaca was a far better place to look'. This literal change in direction led to the isolation of a number of influenza type A viruses.

Influenza type A viruses exist in a variety of subtypes with different markers for the two surface antigens, hemagglutinin (H) and neuraminidase (N). Neuraminidase was first isolated and crystallized by Graeme from a type 2 or N2 virus. An active site was identified that if 'plugged' by a drug would stop the enzyme working and therefore stop the virus multiplying. Most importantly it was discovered that this site would be present on all N subtypes. The drug developed from this research, Relenza, is used worldwide but can only be administered by puffing into the lungs so the challenge was to discover a drug that could be taken as a pill. Once again Graeme's work came into play.

'We discovered an N9 subtype in the Great Barrier Reef birds which provided the best neuraminidase crystals ever obtained', says Graeme. In an attempt to get even bigger and more illustrative crystals particular conditions were required. 'Basically we sent the crystals into space to the Soviet space station Mir to see if they would grow better where there was very little gravity', says Graeme. 'Results were a little disappointing, with the crystals only slightly higher quality than those grown on Earth'. Nonetheless the data from the study of these 'beautiful' crystals led to the development of Tamiflu, the first antiviral that could be taken orally and is our current best defense against the threat of bird flu.