The World We Live In
"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 his entire series here.
On wondering about the last ten essays.
Scientists are asked by journals to give their opinion on a manuscript that has been submitted to them. It’s called peer review and is a filter to see if the work is solid and really does what it apparently says it does. Generally, if the reviewers align, the manuscript is accepted for publication. Peer review is invariably anonymous and there may be between two (typically) to five reviewers per manuscript. Many a journal editor, particularly among the high-profile journals, will tell you they may ask five reviewers to look at the manuscript in the hope of finding just one who will find the weak spot.
Science journalists tend to feel a published paper is gospel allowing them to comment on it if it interesting. It isn’t. Real peer review starts following publication and it can be brutal.
Depending on the topic tens to hundreds of colleagues with specialist knowledge can read the science, applaud it or find a fatal flaw that escaped the peer reviewers. Sometimes the collapse is rapid.
Other times corrections result. Occasionally the authors themselves find a flaw and retract the paper.
That said, retractions are rare.
Most often insiders simply know.
Science, especially biology is very hard to fathom. Fortunately, the endeavor advances by experimentation, or more colloquially, trial and error. It is easy to comment and criticize. After all, armchair politics is a sport practiced by billions, although journalists are among the most voluble. However, if ever their questions and criticisms are turned on themselves, aka what do you think, many duck or do a poor job.
So, what are the questions behind the GOF controversy and what can be done realistically? On wondering will have a go.
The big questions post-COVID are what will the next pandemic look like, and how can we prepare for the inevitable next one? Easy! Answers could easily run to millions of words although the second is way easier than the first. So, to the first. Nobody has ever predicted any pandemic accurately. At best we’re talking about possibilities. Not quantified probabilities.
Common knowledge suggests a respiratory virus, but this is biased by history. AIDS and hepatitis C are less readily referred to as pandemics. Could antibiotic resistance bacteria be classified as multiple pandemics given that we’re at 4.95 million deaths per year globally.
If we use precedent and don’t get pernickety, then it will probably be a respiratory virus like a flu or coronavirus. When? The interval between natural flu pandemics is 8 to 41 years, so on this basis alone were already in the next flu pandemic interval – 2009 + 8 years brings us to 2017. It is eminently reasonable to expect a flu virus pandemic between now and 2050. Not sure that will help a health minister or WHO.
Which flu virus? No idea. The aquatic bird flu virus reservoir, mainly ducks, is huge. Surveillance has identified at least 14 strains that have crossed over to humans all of which resulted in dead-end infections although more could. For the moment H5N1 bird flu represents a low risk for humans. And that’s all that can be said succinctly about flu.
Another bat coronavirus? Of course, although the unknowns surrounding the origin of the COVID virus makes this much harder to assess. There are many animal respiratory viruses - not flu or coronaviruses - which could crossover to humans. Certainly, the phenomenal density of livestock is asking for problems. The economic loss due to microbial infections is already huge so changes are needed to animal husbandry.
Much is written about the stress of climate change, deforestation and increased human contact with wild animals. In turn this is seen as dangerous for humans. Can we be more accurate? There are plenty of hand waving arguments, storytelling and much aplomb, but there are too many unknowns that preclude making closer calls.
That said, there is no need for the blues. Humanity is over 8 billion. We’ve been successful as top dogs - life expectancy at birth is huge compared to only 200 years ago. Smallpox and rinderpest viruses are eradicated, while the polioviruses are almost banished - by vaccination please note. Perhaps dwell on that sentence. For a moment
By contrast, wars…
Let’s remain focused on the war against microbes. We should not be afraid of being realistic. Science does make predictions, famously those arising out of Einstein’s theory of relativity which were ultimately realized. That said, relativity and quantum theory have not yet been squared after 100 years.
In biology, there are strong stochastic and founder effects that are hard to handle. Every genome in the chain from bacteria to humans must be viable and derived from the previous genome. The evolutionary biologist John Maynard Smith had a wonderfully simple illustration of this: WORD -> WORE -> GORE - > GONE -> GENE. Each word on the chain is viable. This important paper was recently celebrated 50 years later.
Along with mutagenic PCR and easy genome synthesis, the exploration of sequence space can occur at unnatural speed. This was highlighted by the 2018 Nobel Prize in Chemistry being awarded to Francis Arnold “for the directed evolution of enzymes” – basically warp speed evolution of enzymes.
The application of accelerated evolutionary techniques to viral genomes may well generate states that natural evolution cannot access. This doesn’t necessarily make them more dangerous – the brutal toll taken by natural human microbes across the ages is humbling enough. Warp speed genetics might make the findings harder to appreciate, but as prediction is hard for natural pathogens anyway, there’s essentially little difference. For the moment.
Biology doesn’t work like engineering, something that cannot be overemphasized. For example, the giraffe’s left recurrent laryngeal nerve is about 5 meters long as it loops under the aortic arch. No engineer would design it that way. Or if they did, their boss would soon pull them up. Furthermore, there is rarely one solution in biology. Even the genetic code, once thought to be universal, is no longer, although chiral amino acids in proteins are unique. The eye and echolocation have been invented 40 times or more.
There are endless configurations for viral and bacterial genomes. There is even something called the bacterial pan-genome. The interaction with the immune system can result in acute, chronic and lifelong infections. Many microbes encode genes to take out or weaken the immune system. Some kill the host although transmission must be accomplished before. Others are apathogenic, so much so that blood transfusion services do not screen for the small anelloviruses which infect more than 90% of humans.
Virologists have wanted to predict the next seasonal flu strain for ages. Some still do. So far, their work hasn’t trumped field surveillance. But it is not just that. For more than 30 years scientists have been talking about emerging infectious diseases. There is a well-respected journal by that name. Quickly everybody’s virus became an emerging infection which led to inflationary re-emerging infections. There is even a journal called Transboundary and Emerging Diseases, a pleonasm as emerging diseases never respect boundaries.
Not surprisingly emerging infectious diseases encompass rapidly mutating viruses, simply because they were changing genetically. Evolving in the Darwinian sense is different. Just take one example, hepatitis C virus. The all-important envelope protein sequence can change by up to 30% even though the virus’s ecological niche, the human liver, hasn’t budged. Actually, this can be said for most viruses.
Emerging infections was a trendy term post-HIV that stuck. A bit like GOF. A few novel and truly emerging infections were among the pack, but most were not. It gave the impression of handling change, but it was mainly synonymous with tracking change of well-established viruses, which is necessary only up to a point. But as we have seen, genetic change does not imply danger for humans (Getting it right).
We’d do well to abandon the mirage of predicting the next pandemic. This means that once a pandemic starts, quick foot work will be key. And this depends on rapid data sharing and some luck.
Once in the early days of a pandemic, what about novel small molecule therapeutics? These take years to develop because of toxicological and pharmacological screening and iterative refinement meaning they will arrive too late. However, we can be sure existing drugs will be tested against a new microbe and hopefully we’ll be lucky. Monoclonal antibodies? This is a mature field and industry can make them at scale. They are expensive. Some off-the-shelf drugs and monoclonal antibodies were seen in action during COVID.
Vaccines? There are fewer commercially available vaccines than there are needed vaccines. Some are notoriously difficult to make. Take HIV. Forty years and billions of dollars of investment later, we don’t have one, but not for want of trying. It might be useful to make three lists of microbes for which we don’t have vaccines. One for microbes which experience suggests we have a reasonable chance of making a vaccine; one for microbes for which making a vaccine may prove difficult and one for those that are damn difficult - an obvious euphemism.
This might be painful to admit although the knowledge is already in the public domain. So, when the next pandemic hits we’ll not have to suffer silly remarks like ‘we’ll have a vaccine within two years.’ Any journalist can fact check. More funding would yield some big rewards.
The world was very lucky indeed that the COVID vaccine was as efficient as it was. This was not a given. Oddly it didn’t stop transmission but impacted disease severity and death which is what counts. A vaccine providing long lasting immunity to COVID variants would be good to have, much like a highly efficient flu vaccine, although it brings up the question, is this even possible? Such investments will be far more beneficial than computer driven predictions or DURC/GOF virology.
So how about the easier of the two questions: how can we prepare for the inevitable next one? More surveillance, reactive data sharing and transparency would help enormously with political considerations taking second place to the fight to save lives.
On top of this, microbiologists mustn’t pretend they know, they can predict anything accurately in the very early days, or will have things under control in a jiffy. We were blindsided by SARS-CoV-2. Nobody had described even a close cousin in bats before 2019. More field work is needed. Science administrators must not kid the public or government.
The next pandemic will be a race between science and the microbe. The outcome and the human price paid will be unclear for a while.
This is the unpredictable world of microbes we are part of. You don’t like it? Tough.
Aside 1
Nothing is said about the ongoing Anthropocene mass extinction of animal species, and with them their microbes. Good news from Homo sapiens’ perspective.
Aside 2
By the by, can there logically be an expert when a new microbe bursts on the human stage?
Aside 3
I wonder as I wander is the first line of a New England folk hymn that was set as a Christmas carol.
It is a lovely description of curiosity. Worth keeping in mind in this crazy world.
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The part about vaccines was very interesting.
Your statement "We’d do well to abandon the mirage of predicting the next pandemic." makes perfect sense but runs into the problem of 'Politicians's Logic' (from the BBC's "Yes, Prime Minister"):
1: We must do something
2. This is something
3. Therefore, we must do this.
And the field of "emerging" diseases seems to be thriving, with every hordes of new viruses characterized as "having the potential of zoonotic spillover",
Thank you for these insightful essays, Professor Wain-Hobson. There's more than enough hubris to go around in the denials of dangers of technologies for which disasters would be (or have been) largely inadvertent. But alongside this are deliberate attempts, or proposed ones, for improving the human species using similar putatively problem-free methods. Please see: https://www.independentsciencenews.org/commentaries/children-from-gamete-like-cells-dishing-up-a-eugenic-future/