Professor Eddie Holmes: The split-second decision to reveal SARS-CoV-2 to the world

“Oh shit,” Professor Eddie Holmes recalls saying. “SARS is back.”

It was 5 January 2020, and he was looking at the SARS-CoV-2 genome. He was meant to be heading to Sunday brunch on Sydney’s Northern Beaches, but instead he had just received an urgent email from China.

It had come from his long-time friend and colleague, Professor Yong-Zhen Zhang, a virologist from Fudan University in Shanghai, who having worked two nights straight with his team, had just sequenced the genetic instructions for a global disaster from samples collected from patients in the city of Wuhan.

At this point, it was still early days. The COVID-19 story remained contained in the foreign news section: just 59 suspected cases — all of whom were quarantined — with a further 163 contacts being closely monitored by Chinese authorities.

But Professor Holmes was alarmed by what he saw and called his colleague back to discuss the results.

“It was immediately clear that this was a human respiratory virus,” he tells Australian Doctor.

“But obviously none of this was going to answer the key question we faced: whether people would shed the virus only symptomatically, like SARS-CoV-1, where overall case numbers didn’t go much beyond 8000.

“Or was it going to happen asymptomatically, where controlling its spread would become far more difficult.”

So, both of them waited expectantly for the Chinese Government to make an official announcement of their findings.

They believed it was imminent. Their work would allow scientists to develop effective tests for the virus, support medical treatments and, hopefully, help in the development of new vaccines.

But no announcement came. Just silence.

After six days, they took matters into their own hands.

On 11 January, Professor Zhang, just as he was boarding a plane heading to Beijing, got a call from Professor Holmes asking permission to publish the sequence.

As the cabin crew began asking Professor Zhang to switch his phone off pending takeoff, he made a split-second decision, calling one of his staff at his Shanghai lab and telling them to email the sequence over to Professor Holmes in Sydney.

Within minutes of the file arriving in his inbox, Professor Holmes was on the phone to another colleague, the Scottish evolutionary biologist Professor Andrew Rambaut, who ran an online discussion forum virological.org dedicated to the “analysis and interpretation of virus molecular evolution and epidemiology”.

Although it was after midnight in Edinburgh, Professor Rambaut was told the genome sequence was on its way and to publish it immediately.

Such was his sense of urgency, Professor Holmes says he forgot to check the contents of the email from the Shanghai lab before forwarding it on.

“It could have been DNA from a blowfly,” he says.

But less than an hour later, the SARS-CoV-2 viral sequence was in the public domain. The post included the preface: “Please feel free to download, share, use, and analyze this data…”

And that’s what the scientific community did.

Both Professor Holmes and Professor Zhang were lauded as heroes.

Forbidden fruit?

An evolutionary virologist at the University of Sydney’s Institute for Infectious Diseases, Professor Holmes says he owes his interest in science to his high school science teacher.

“We had this textbook in class, but there was one section that we were told not to read.

“I guess if you tell a 14-year-old kid, ‘Don’t look at that,’ your natural instinct is to go, ‘I’ll take a look.’

“The chapter in question was the theory of evolution. My teacher, who was a creationist, said it was bad; therefore, I was thinking it might be quite good … It probably was biblical for me. It was sort of like a forbidden fruit.”

So Professor Holmes bit the apple. But there was no fall. It was the beginning of what was to become a stellar academic career.

He went on to complete a Bachelor of Science in anthropology at University College London in 1986.

Four years later, he earnt his PhD in zoology at the University of Cambridge. His thesis was on the pattern and process in the molecular evolution of primates.

He then moved to the US to complete postdoctoral research in evolutionary genetics, but this time, his subjects were fruit flies.

“One of the defining traits of the insect,” he explains, “are the bristles on the back of the head.

“It’s a very simple genetic control. You count the number of bristles and work out how many mutations in the genes have changed that number and then how they interact.”

He grew bored.

“I was not cut out for it,” he acknowledges.

The trigger for the change in his professional life, which would ultimately make his name, came during the height of the AIDS epidemic in San Francisco when he heard a talk by the geneticist Professor Andrew Leigh-Brown on the way evolutionary genetics could be used to track the spread of HIV.

“I thought to myself, ‘God, that’s just so much more interesting than what I’m doing’.

“Viruses are terrible things, but for an evolutionary biologist, they actually give you an insight into how evolution takes place.

“They evolve over a million times faster than human genes, which is partly why they’re a problem, but it also allows you to track their spread very quickly.”

He soon packed his bags and relocated to Edinburgh University, where he took up postdoctoral research with Professor Leigh-Brown in a city racked by its own AIDS crisis.

“We really make an effective science out of it,” he says.  “We really wanted to see if we could use virus gene sequence data to track the spread of the virus.”

In 1995, they published a paper in The Journal of Infectious Diseases where they described using the evolutionary analysis of virus gene sequences to document the origin of the HIV epidemic in Edinburgh and its spread through the city.

Decades later, the evolutionary methods they helped develop are being used to uncover the origins of SARS-CoV-2 variants and track their spread both locally and globally.

The origin question

The origin question for SARS-COV-2 quickly became contentious, with the initial voids in knowledge during the early days of the outbreak filled with various theories, most of which seemed influenced by the turbulence of geopolitics rather than facts.

Certainly, the Chinese obsession with control didn’t seem to help.

But like the virus itself, there were many variants — ranging from SARS-CoV-2 being engineered, it being deliberately released, it being spread as a result of a lab leak to the more mundane idea of zoonotic transfer via the wet markets in Wuhan.

Professor Holmes, whose research expertise focuses on the mechanisms through which viruses jump species boundaries, has played a leading role in the debate, writing a paper in Nature in March last year, where he and his colleagues unpicked the various claims being thrown out.

His considered view — both then and now — is a blunt ‘no’ to the idea of a genetically engineered virus.

A lab leak, while possible and not an unknown occurrence, is also not well supported by known facts.

The most likely explanation? Natural zoonotic transfer. He says it may take some time to identify the specific mechanism, but it remains, as yet, the best explanation we’ve got.

Was the pandemic inevitable?

The threat of viral outbreaks to the future of humanity has long been obvious to scientists and perhaps should have been known to the rest of us, at least since microbes put paid to the first alien invasion attempt in War of the Worlds.

But until 2020, the warnings that were flagged, at least at a political level, were ignored. Terrorism saturated the political consciousness.

Professor Holmes says it was only a matter of time until SARS-CoV-2 or a similar virus emerged.

“The way humans live today, a pandemic was absolutely inevitable.

“Deforestation, climate change, global travel, urbanisation — all those things feed pandemics.”

Did he expect the global damage — 268 million cases, 5.3 million deaths and counting — to be on this scale?

“No way, I was shocked.”

He recalls complex feelings as a scientist when viewing the virus’ genetic code. A mix of excitement (because this was something new) and concern (because this was something new).

Only a few dozen cases of the mysterious pneumonia-like condition had been reported by China to the WHO, and the extent of human-to-human transmission was not at all clear.

But as the virus then spread to other countries, his initial wonder was replaced by what he describes as “blanket fear”.

“By mid-February, everything that has happened I could see happening — I knew the world would shut down.”

Professor Holmes marvels at the speed at which science and medicine have moved in response. The creation of diagnostic tests, the emergence of treatments and obviously the wonders of the vaccines themselves. And he is acutely aware of his own role and the role of Professor Zhang in these advances.

Rectification

But with this is a very personal pain.

His is one of Australia’s biggest names in science. He has authored 658 peer-reviewed papers; his publications receiving some 101,000 citations. This year, he was handed the Prime Minister’s Prize for Science, worth some $250,000.

But he knows the risks he took in an open society when requesting the genome sequence in that phone call to his colleague. For Professor Zhang, working under an authoritarian government seemingly paranoid about international opinion, it has been different.

The two have known each other since 2011.

“He always calls me his brother; he’s a very good friend of mine,” says Professor Holmes.

The day after the publication of the genome sequence, the Chinese Government did make an official announcement about their work. But on the same day, Professor Zhang’s lab was also shut down for two weeks by the Shanghai Health Commission for so-called “rectification”.

Professor Zhang has subsequently disputed media reports that it was retaliation for his alleged transgressions.

It remains unclear whether he has faced further punishment for his actions.

Professor Holmes hints that the repercussions are “ongoing” but says he can’t go into detail for fear of complicating matters for his friend.

“It’s been a very difficult time for him since we released that data. What he did was the right thing to do and a brave thing to do.

“It’s much easier for me sitting in my house in Sydney to do things: we’re allowed to communicate how we want; it’s a very different situation in China.”

Professor Zhang’s predicament is not unique, he says.

“I don’t think the scientists in China are doing anything wrong; it’s just what they’re allowed to say.

“It’s a very frustrating situation to be in, and I endlessly bang my head against the wall about this,” Professor Holmes continues.

“We should be against authoritarian regimes for many reasons, but if there’s one thing that COVID-19 has taught us, it is that if we want to mitigate and prevent pandemics, we need to share data as openly and rapidly as possible.

“Going forward, openness needs to underpin the science we do, and anything that inhibits that will be bad for humanity in the long term … If openness is not there, the world will be a much less safe place.”

Got something to say about COVID-19? Join our new AusDoc Coronavirus Group.