Skyfall

"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.

Since January 2024, Dr. Wain-Hobson has written weekly essays for Biosafety Now discussing risky research in virology. You can read this entire series here.

Late afternoon skyscape, north-west France, 2024

On reading recent reports of H5N1 avian flu virus infection of cattle and a goat in Minnesota provoked a flashback to an article of his published on May 5, 2015 in the German Sunday newspaper Frankfurter Allegemeine Zeitung. It was never published in English. Part of it is given below with some rewriting.

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An alarming outbreak of bird flu is decimating chickens and turkeys in Iowa and 11 other states right now [spring 2015]. In this tragedy for American poultry farmers, ten million or more egg-laying hens will have to be killed. The culprit: the avian H5N2 influenza A virus. It has shown up just as another avian influenza virus, H5N8, is doing the rounds in five states. Some simple number crunching might help put the concern about their impact for Americans in perspective.

Avian influenza is an enteric infection of the gut in birds, unlike influenza in humans which infects the respiratory tract. While terrestrial birds like sparrows, magpies and pigeons do get flu virus infections, ducks and shorebirds constitute the largest reservoir of influenza A viruses in the world. The virus emerges with the semi-liquid guano.

Birds do their thing in the air, on the ground or over oceans, lakes and ponds. Impact might make aerosols which could be inhaled by grazing animals. The total number of birds is estimated to be 40-130 billion worldwide. If each poops around 2 ml per day, this means that between 80,000-260,000 metric tons of poop falls to the ground every day.

The seasonal rhythm provokes massive migrations of ducks, geese and birds along corridors called flyways. A typical example is from West Africa to Northern Europe and back via the Strait of Gibraltar. In North America there is the Mississippi flyway, while on the other side of the Pacific, the East Asian-Australasian flyway. As they rest on lakes, ponds and marshes, it is not surprising lakeshore water is full of flu viruses.

When guano falls on seawater, blue whales, dolphins and seals can come down with avian influenza infections. These mammals pick up the virus from ocean surface water. Their carcasses are occasionally found washed up on shores. The extent of the 2014 Baltic Sea seal epidemic caused by an avian H10N7 influenza virus is a case in point.

This should not be a cause for panic. We have more than 100 years of experience with human flu. Humans have been hunting birds since time immemorial. Flu pandemics are rare, five since the 1918 and confined to just three influenza combinations of H and N - H1N1, H2N2 and H3N2.

Other combinations of influenza H and N can occasionally poop up in humans. Our surveillance systems are so good – well, they can always be better – that a single case of human H6N1 influenza was picked up in Taiwan in 2013. A look-alike virus had been circulating in Taiwanese chickens for some years before.

Nearly always these bird flu infections of humans are rare and the virus does not spread to other humans. Because of this they are called dead-end infections. The viruses either succumb to the immune system of individuals who recover from infection, or else they die with the patient.

Dead-end infections are not new. Viruses are knock, knock, knocking on our door, always have, always will. Indeed, this is so for every species on the planet down to bacteria. Human rabies infections are dead-end infections and number around 55,000 per year. Without post-exposure vaccination they are fatal.

Evidence of onward transmission of avian influenza viruses from dead-end H5N1 or H7N9 infections in man is scant. That doesn’t mean that these viruses cannot transmit between humans or never will. It just means that it is not easy for these viruses to adapt to human respiratory transmission. A couple of recent hardcore virology papers confirmed this.

We must not confuse dead-end human avian influenza infections that, for the moment, number a few thousand cases over 20 years, with seasonal flu where a sizeable fraction of the world’s population is infected and up to 500,000 people can die in a year.

Equally, it is unwise to underestimate a virus. Flu viruses naturally mutate – so much so that each time they copy their genome one error frequently occurs. If this may appear to some like shooting itself in the foot, remember that influenza A viruses are success stories by any metric. Witness the current outbreak in America.

We have to find a balance between vigilance and complacency which is never easy. Fear mongering – for example, stoking fears that the next human flu pandemic could break out of Iowa - doesn’t help anybody. [This didn’t happen.] As we know, many people don’t think clearly under stress. This is not the first time avian influenza has struck the US even though this is probably the largest outbreak for last 30 years. Flu viruses have literally been falling out of the skies for years.

While this outbreak of bird flu is ongoing, we have seen calls for great prudence in the use of topflight, state-of-the-art gene technologies to modify genomes, including the genomes of human embryos. These calls came out came out only a few weeks ago in the world’s leading journals – Nature and Science. The page was turned last week when a Chinese group came out with a paper doing just this. Where was the debate? Where is the paper trail from the funders and ethical committees this past year discussing the pros and cons of genome editing? A red line has been crossed with remarkable alacrity, while the watchdogs were asleep.

The major difference between genome editing and DURC influenza virus research is, to be blunt, that humans don’t reproduce as fast as viruses. Some animal viruses can replicate in as little as 6 hours. Humans take 36,000 times more time.

And let’s not forget that human error and maliciousness are part and parcel of the human condition. A bird virus engineered by humans to become transmissible between humans by the respiratory route could go round the world in a matter of weeks infecting hundreds of millions of people.

We’ve just been through a harrowing Ebola crisis. Nobody knew that the Ebola virus could cause an epidemic on such a large scale. A novel man-made influenza virus, to which humans have no immunity, would cause havoc with poorly resourced health care systems – not to mention that it could kill millions of people around the world.

Rather than contemplate the apocalypse, let’s be prosaic and down to earth. Five cases or deaths resulting from one of these novel human influenza virus experiments would stop the work in its tracks. As one research institute director said, “one infection in my place and I’d be out of a job.”

Why are we waiting for the accident to happen? Because this is par for the course in contemporary society where powerful interest groups can stymy reason and prevention. There is nothing good to be gained from gain-of-function influenza virology. Such a flight from reason hurts and is not scientific.

Avian influenza viruses have been raining down on the planet every day for centuries – and we’ve survived albeit at the cost of regular pandemics. We don’t need to create super viruses.

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Aside 1

Despite the 9 year hiatus, H5N1 bird flu still comes and goes. There may be moments of déjà vu for some readers. Other flu viruses spill over, like H1N2, the first human case for 2024 in the US was recently reported.

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Aside 2

Unlike mammals which excrete waste nitrogen in the form or urea, birds excrete nitrogen as uric acid which is about 2800 times less soluble in water than urea. Hence it readily crystalizes. The crystals reflect light giving guano a white aspect.

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Aside 3

What about the pigeon droppings on your car? Humans can contract cryptococcosis, histoplasmosis and psittacosis by breathing in the dust created when cleaning droppings. That said, the risk of pigeon-related diseases is rare. A paper can be found here. Something to think about when next in Piazza del Popolo or Trafalgar Square.

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Simon Wain-Hobson is an emeritus professor at the Institute Pasteur, Paris, from which he retired in 2021. He and his colleagues were the first to sequence the genome of HIV, and Wain-Hobson has published more than 230 papers on virology and cancer.