A beach littered with dead birds provided a "eureka" moment for Otago alumnus Professor Robert Webster who, over the following decades, became a world authority on avian flu, its transmission and its implications for the future.
South Otago, the Great Barrier Reef, the live bird markets of Hong Kong, and St Jude Children's Research Hospital in Memphis may all seem like completely unrelated places – until, that is, you align them with a long and illustrious career.
For Professor Robert Webster, his more than 60-year journey from being one of a family of 13 children on a farm near Balclutha to being an international authority in avian influenza has been full of twists and turns.
Having initially followed his older brother into studying Chemistry at the University of Otago, Webster's career path took its first unexpected turn when Molly Marples, wife of Zoology Professor Marples, spoke to the chemistry club about the new Department of Microbiology she was heading up.
"She talked about microbiology – micro-organisms, bacteria, viruses, yeast – and captured me, as it were, to the idea of putting together chemistry, disease and animals. So I moved my focus to microbiology."
Armed with a BSc in Microbiology, Webster headed to the Wallaceville Animal Research Centre where, as New Zealand's first veterinary virologist, he began to isolate viruses in many local animals and also completed a master’s degree, researching the ORF poxviruses in sheep.
The opportunity to go to Canberra and work with poxvirus authority Professor Frank Fenner in a new School of Microbiology at the Australian National University appeared too good to pass up. However, his career path was about to take another twist.
"I can remember sitting in his office the day I arrived and he said: 'I'm going to get you to work on influenza'. It was a great disappointment,” the 84-year-old Webster adds with a wry smile. "But what did I do for the rest of my life? I worked on influenza."
Webster embraced his new direction, going on to publish more than 600 original articles and reviews on influenza viruses. He was made a Fellow of both the Royal Society of New Zealand and the Royal Society of London, and a member of the US National Academy of Sciences. He has also given his name to the Webster Centre for Infectious Diseases and the Webster Family Chair in Viral Pathogenesis at Otago.
That unexpected new direction also produced a lifelong collaboration with leading Australian biochemist Graeme Laver.
A beach walk provided a "eureka" moment when they found the shore littered with dead mutton birds and wondered if they had died from avian flu.
"We'd just had the 1957 Asian flu pandemic and the big question was where did these pandemics come from?
"There were two possibilities. Either the virus simply went through massive mutations or it came from another source. Our idea was that it probably did come from another source because there were influenza viruses showing up in pigs and chickens and ducks around the world, but no one had really connected them."
World Health Organization (WHO) funding allowed them to go to the Great Barrier Reef where they identified healthy seabirds carrying antibodies related to the pandemic strain.
"It showed two important things: flu was present in perfectly healthy seabirds and, secondly, you got the virus out of the poop, not the respiratory tract. We proposed that this was the source of the influenza viruses that went into pigs and humans."
Webster moved to Memphis, Tennessee, to continue his work, confirming that aquatic birds are the reservoirs of influenza. By the early 1990s interest in the flu was waning – that is until six young people in China died in 1996 and the world suddenly took notice.
Detective work by a team recruited urgently by Webster identified ducks and other birds in Hong Kong's live markets as a source. Authorities closed the markets, stopping its spread there, but it survived in ducks in China and remains a problem today.
The virus, now known as H5N1 (bird flu), has become endemic in South-East Asia, Indonesia, Vietnam and China and has spread to Europe.
Generous funding from the United States National Institutes of Health (NIH) enabled the formation of the Centre of Excellence for Influenza Research for Hong Kong and Memphis (St Jude Children's Research Hospital), headed initially by Webster. Eventually NIH developed six centres for research, each with a multi-million dollar budget.
Their work has proved vital in the development of more effective vaccines. They have also served as the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds – providing information on animal viruses that pose a threat to humans.
Although Professor Webster has retired from his role, he recruited Dr Richard Webby, another Otago graduate, who now heads up the programme of excellence for influenza research.
What would it take for a bird flu like H5N1 to not only jump to humans, but also be transmitted human to human?
Although the work of Webster and others in the field means influenza is far better understood, that troubling question remains.
Epidemics such as the Spanish flu of 1918, which is now known to have had avian origins, provide a deadly example of what could happen.
DNA segments from bodies buried in the Arctic permafrost enabled the sequencing of the 1918 virus and scientists have remade it in high containment facilities.
Although a controversial step, it is one Webster is happy to defend because it helps them understand crucial things about the virus.
"Why were they so virulent? Why were they so lethal? To understand that we need to understand the mechanism. If you want to have drugs and strategies to control it you have to have access to these bad viruses," he says.
"The question with bird flu is would these viruses ever have the ability to transmit human to human? If they transmit from chickens to humans they kill 60 per cent."
Research has now established that if three specific molecular changes occur in the virus it can transmit from one ferret to another. All three changes have been found in nature, but never together.
Webster says “all hell broke loose” when the researchers who did the work tried to publish. The National Science Advisory Board for Biosecurity (NSABB), the group concerned with bioterrorism, said it was too dangerous.
"Eventually it was decided it was so sophisticated that enviro-terrorists wouldn't be able to do it," he says.
"They published, but strict rules were put into place for scientists working with these organisms."
However, in 2015 several accidents – including The Centres for Disease Control mistakenly sending H5N1 to a lab and the army sending out live anthrax – resulted in the US Congress halting the work while guidelines are rewritten.
Webster believes that it is urgent to resolve the guidelines for gain-of-function research because countries like China do not face such restrictions.
"It needs to be examined carefully because the rest of the world is going ahead much more quickly," he says. "There are huge ethical decisions to be made in biology."
On the flipside, research like this could open the way to a universal vaccine for flu.
"You could have a universal vaccine in one shot, like with the measles. Influenza vaccines are only 50 per cent effective so we need much better vaccines."
New drugs are also needed because currently there is only one effective drug for flu, while there is a plethora of HIV drugs.
There is also scope to learn more from the genomes of hosts to understand, for example, why ducks show almost no sign of the disease while a chicken will die from the same strain, he says.
"What's the difference? We now know the chicken, during genetic development, lost the RIG-I gene – a gene that makes interferon. The duck does it, the chicken doesn't, so the chicken dies.
"This is just one of a whole host of genes.
"Many animals, such as sheep, don't get influenza, so what are the genes that prevent them from getting it? Could you put those genes into the pig, into the chicken and create genetic resistance? That will happen."
Story: Mark Wright
Photo: Alan Dove