Explainer: Now We’ve All Got Skin In The Game, Here’s Everything You Need To Know About Viruses And COVID-19

As the COVID-19 crisis gathers pace, Geoff Russell explains in simple language what is happening, how and why, and what we can do to reduce the risks into the future (hint: it starts with ending intensive farming for meat).

The boy who cried wolf is one of the most enduring of Aesop’s fables… morality tales attributed to a Greek slave living some 2,500 years ago. It’s about a boy who cries ‘Wolf!’ in the absence of a beast. Do this a few times and people will soon stop reacting, other than to get really annoyed.

Virologists have often been accused of crying wolf for well over 20 years now, more than long enough to become annoying. But 20 years is a short time in the history of diseases and the fact that a viral wolf has arrived so quickly doesn’t bode well for the rest of the century and beyond; except perhaps that our greenhouse gas emissions will certainly dip. But not enough to be decisive.

The viral wolf was preceded by plenty of lesser cubs; SARS, Ebola, Mers, Swine Flu, H5N1 bird flu, and Zika, to name the most widely publicised of them. But the lessons weren’t learned.

One possible upside to the present viral disaster could be that we learn to pay experts a little more respect; not just virologists but even those bleating on and on about antibiotic resistance and the most boring of all, the climate change experts!

So why have virologist been warning us? Thom van Dooren’s recent NM article gave a great survey of the role of intensive agriculture and our exploitative relationship with wildlife – factory farms, wet markets and bushmeat. But how? How do viruses jump species?

If you don’t understand the mechanisms, then why would you bother with the hard work of changing our food supply, retraining farmers, cooks and consumers? Everything becomes clearer if you understand the mechanisms of transmission, and while the detail is devilishly complex, the basic principles aren’t that hard.

How viruses work

Think about the measles. It’s been around forever, right? Wrong. It’s actually quite new. We got it from cattle by a very basic biological process (more on this below).

Measles is a virus and viruses are typically exquisitely tuned not just to a single species, but to very specific cell types in that species. For example, a cold virus doesn’t infect your feet. Here’s how it works.

A virus is just a bundle of either RNA and DNA – two different types of genetic material – and bugger all else. Put bacteria in a dish and feed them and they grow. They’re alive, and looking to stay alive. Not so viruses. They aren’t actually alive and can’t reproduce without help.

A virus particle needs to get into your cell to reproduce. ‘Breaking and entering’ is the start of the process. Once inside it hijacks what it needs, typically producing hundreds of copies inside the cell. The cell eventually becomes overwhelmed and splits open, releasing a swarm of new virus particles which go on to infect still more cells.

The surface of the cells of every species is slightly different. Think of a door lock. The surface of any cell is peppered with locks. The locks on rat cells are different from the locks on human cells, which are different from the locks on brown snake cells, which are different from the locks on shark cells.

Just as the surface of cells contains locks, the surface of a viral particle contains keys. In all the Covid-19 imagery around at the moment, the viral particle looks like a round ball with spikes on it. Each spike is a key (the key is actually just a protein) and its shape is determined by the genetic material of the virus. If its key doesn’t fit the locks on your cells, then the viral particle can’t get in.

The genetic material inside the tiny viral particle is even smaller. Our genetic material contains three billion letters; they spell out ways to make somewhat more than 20,000 proteins.

The virus causing Covid-19 has just 29,000 letters with some 10 genes which can make about 30 proteins. The spike (the key that unlocks your cells) is one of those proteins.

Despite what I said about viruses mostly infecting a single species, it’s not all that unusual for one viral key to fit locks on closely-related animal species. The genetic closeness of species and the similarity of locks is critical to understanding how viruses jump from one species to another. But it’s not the only criterion.

A recent study looked at 1,446 viruses that infect 1,560 non-human mammals. Their goal was to develop a measure of how likely various pathogens (a bacterium, virus, or other microorganism that can cause disease) might be to cause us a problem in the future.

Nothing is likely to jump from a species we rarely come into contact with. And nothing is likely to jump from animals to us that are genetically separated by a wide margin. That’s one reason why the study didn’t consider reptile pathogens and hosts. This was a high-level study. Other work focuses on the fine details of how viruses might get into cells.

Mutations and other genetic changes

Once the viral particle is in the cell, it opens up and spills the full text of its genome – an organism’s complete set of DNA, including all of its genes – into the cell. The letters of the text are joined together, but get hit by the same storm of free radical chemicals.

These chemicals are generated by energy production in our cells and cause about 10,000 pieces of damage to our own DNA every day (most of which is fixed by repair mechanisms).

So the viral genetic material will get damaged, meaning letters will be changed. There are, so far, over 900 copies of the SARS-Cov-2 viral genome (the virus which causes COVID-19) on the growing international databases. Why so many? Don’t you need just one? Or one for each strain? And what exactly is a strain? We’ll answer these questions soon, but first some simple arithmetic.

I mentioned that the DNA in a human cell suffers 10,000 or so pieces of damage per day. So how much damage will the RNA in a SARS-Cov-2 virus particle suffer? It’s about 29,903 letters long; and it’s RNA rather than DNA, but that’s not important, yet.

So if the 3 billion letter genetic material of our cell gets 10,000 pieces of damage per day, then SARS-Cov-2 material will probably suffer a similar rate of damage… meaning about 10,000 divided by 3 billion multiplied by 29,903; or about 0.09 pieces of damage per viral particle per day. So most viral particles are unchanged… but about 1 in 10 gets a change in a letter.

But viruses like SARS-Cov-2 have far more changes than this, so what else is happening? SARS-Cov-2 doesn’t use the cell’s native mechanisms for accurately duplicating its genetic material; it has its own tools, and they suck. Imagine a vision-impaired monk with arthritic hands and severe dyslexia copying medieval manuscripts and you’ll get the picture.

RNA viruses in general all seem to thrive on sloppy copying of their genetic material. They have evolved high levels of variability, making them brilliant at adapting to anything life throws at them. SARS-Cov-2 has a very long genome for a virus, and one problem long confusing virologists was that it seemed to be too long. The well understood sloppy copying mechanism should have introduced so many errors that this virus should simply have just died out. But it didn’t.

Like others in the Coronavirus group, SARS-Cov-2 looks to have adopted some of the tricks that our DNA uses to reduce error rates; but its mutation rates are still really, really high.

Now here’s a picture. It’s worth thousands of words and plenty of attention.

It looks like a family tree, showing children and their parents; which it kind of is. Focus on the coloured dots. Each represents the genetic material from one (or more) viral samples taken from people who are sick. The branches indicate a change… somebody got infected and the RNA in the virus is ever so slightly different from the RNA in the virus of the person they caught it from.

Most people who are tested don’t have their genome loaded onto this database – these are samples loaded by research teams. Because each genome is short, the chances of multiple pieces of damage is small, and sometimes there will be no damage at all.

No damage means that the virus in you is exactly the same as the virus of the person who infected you. Keep in mind that many of the particles released as each of your cells is infected and bursts open won’t be the same as the particles that infected you; which won’t be the same as each other.

There are plenty of things to notice about this picture:

1. Many of these genetic changes are of no consequence, meaning they don’t change the shape of the spike (the key) or other proteins in any significant way or change the nature of the disease that infected people get. That’s why virologists still reckon there are only currently about 10 types (strains) of SARS-Cov-2 circulating (it was 7 strains a week ago).
2. There are some changes in some related viral samples which virologists reckon are significant enough to mark a branch as significantly different in the tree, as opposed to the many innocuous branches in the image above. The next picture is colour coded according to currently accepted opinions about such strains.

The black box describes the mutations in one of the samples… a slightly bigger blue circle on the right of the image, just above the top right corner of the black box.

It’s not entirely obvious from the image above, but the nature of the changes is random, in the sense of being unpredictable.

Here’s a third image. Imagining the letter of the genetic material laid out in a line, this image shows the number of changes to letters in a few of the 10 genes.

The full image is too wide for a page, so I’ve just picked two genes (the ORF1b gene and the S gene). The little lines on the top count the total number of changes in the letters in the genes across all of the samples. Mostly it’s 1, occasionally 2, and there’s a couple of higher counts.

Lastly, almost as an aside… according to the assumptions of Linus Pauling when he calculated the impacts of radioactive fallout and spawned the anti-nuclear movement, how many dots should there be on these images? Just one.

Pauling thought mutations to genetic material were incredibly rare and happened “perhaps once in a hundred thousand generations,” which is why he thought mutations from radiation were such a big deal. I’ve been banging on about the obsolete science behind the anti-nuclear movement’s fear of radiation for about a decade now, and the pictures above are a terrific illustration of how far biology has progressed in the past 60 years… entirely unnoticed by the anti-nuclear movement.

All of Pauling’s assumptions were wrong, and, of course, he wouldn’t have even dreamed of the dodgy copying methods of viral genetic material reproduction.

Jumping species

Can a mutation change the nature of a viral disease? Yes. A mutation can not only change the nature of the disease, but also the shape of the keys on the surface of the viral particle.

Imagine a cow with rinderpest, a viral disease in cattle. It was eradicated by a global vaccination campaign and officially declared vanquished in 2011.

The rinderpest viral infection in cattle produces diarrhea and nasal discharges, all full of viral particles. Any human not practicing cattle social distancing may come into contact with these. If any of those particles has precisely the right genetic change (caused during the particle’s time in the host cell), then, if that human was incredibly unlucky, the change might allow the viral key to fit a human lock. Bingo. The virus has jumped from cattle to humans.

This happened with rinderpest and the result was measles.

Before vaccination, measles killed an average of 2.6 million people a year. And it would again if the anti-vaxxers had their way.

The process I just described is a little simplified. The first jump will probably not result in long-term human infection. It takes multiple jumps until eventually, one has the genetic material to not just infect a person, but successfully move between people.

In summary, measles is just rinderpest with some small genetic changes that enable its keys to fit human locks. That jump happened about a thousand years ago and has been killing humans ever since. The sequence of events is wildly improbable but if you put enough people in contact with enough cattle over enough time, then the improbable becomes rather more likely.

Just like mumps, which looks to have come from pigs even earlier than measles came from cows. H5N1 bird flu is a deadly influenza from chickens. It has been jumping spasmodically for the past couple of decades, but, luckily never managed to evolve into a sustained killer.

H5N1 bird flu was widely tipped to be the next big pandemic, but it wasn’t (COVID-19 was). But H5N1 hasn’t gone away; we’ve just been lucky. As long as chickens are part of the human food supply at the scale required for a human population of 7.6 billion, it, along with other avian influenzas, will remain a risk.

Virulence

The virulence of a disease is how sick it makes you. The genetic lottery which makes for species jumping is coupled with a genetic lottery which can change the nature of the disease that a virus causes; the virulence lottery.

Over the past 20 years, genome sequencing has enabled virologists to look into this process in excruciating detail. In 1983 a benign avian flu was infecting chickens in a chicken shed in Pennsylvania in the US. Then one night it changed. The change didn’t cause a species jump – it caused a change in virulence; the virus started to kill… 17 million chickens, in fact.

Eventually, virologists discovered that a single change in the genetic material was the difference between benign and deadly. This is like changing a single letter of a novel and changing the entire nature of the book.

While this chicken disease wouldn’t have made the news outside of Pennsylvania, this kind of event has been happening with increasing frequency for decades in the factory farming industry; the industry which gave us swine flu, a mixture of pig, human and chicken genetic material.

For obvious reasons, evolution doesn’t favour viruses which kill before they can spread. But on a factory farm, spreading is easy. Similarly, in our crowded cities, spreading is easy and, as we are discovering, social isolation isn’t simple. Which is why many of the worst infectious diseases are crowd diseases; they are too deadly to spread far in a gatherer hunter society.

Species jumping part II

Just summarising, the process by which a virus jumps species depends on the virus genetic material being changed so that it can infect a species other than its normal host. But viruses have another trick that helps them move around from species to species.

What if you catch two viruses at once? If you’ve been watching the Covid-19 advice on symptoms, you may have seen “runny nose” pop up from time to time. It isn’t on the WHO list of symptoms or the US Centre for Disease Control’s list. So is it or isn’t it a symptom? And what happens if you get infected by SARS-Cov-2 as well as a common cold virus?

You’d have a runny nose in addition to the standard Covid-19 ‘FFC symptoms’: fever, fatigue, coughing. Because colds are so common, more than a few people with Covid-19 will have a runny nose and doctors will have a tough time working out exactly which symptoms are from what.

Apart from complicating the process of working out symptom lists, there’s another thing that being infected with two viruses can do. The two viruses can end up with bits of each others’ genome. Swine flu is a mix of four different viruses. Two is more common, but mixtures of multiple viruses are perfectly possible.

Enter SARS-Cov-2

So how was SARS-Cov-2 formed? Nobody is quite sure, yet. Does it matter?

That depends on whether you think this is just a one-off aberration or just another part of a stream. Interestingly, New Scientist (21st March) noted that Singapore, South Korea, China and Canada were the countries doing best at handling this virus… probably because they’d all had a practice run with SARS.

Virologists have had a pretty good idea of the kinds of processes involved in producing new zoonotic diseases for years; but few were listening. Knowing these processes, coupled with a sense of urgency which this pandemic may bring, should be enough to drive us to change our ways.

Just as this year’s bush fires and the continuing record-breaking temperatures have driven new policies on climate change… okay, granted, that’s not a good analogy. But finding precise sources is what virologists like to do. You can’t stop them and it might well reveal something useful.

So far, there have been three major theories. It evolved in the Huanan wet markets. A ‘wet’ market has multiple species of live animal in one place. People select animals who will then be killed and butchered on the spot.

As a result of the outbreak, the Chinese Government ordered a ban on “all wildlife transactions”. That’s a bit like ordering people not to download pirate movies. It will only work if you can transform the prevailing culture, as well as making it technically really difficult.

Once the mechanisms are explained (above) then it’s easy to see why wet markets are a bad idea and a perfect place to breed new viruses. Throwing different species together, particularly when they are highly stressed, is a perfect environment to give an animal multiple viruses and to spread them to other animals or people.

Of the first 41 cases in China, 28 were in people who’d been to the Huanan wet market. But 13 weren’t, and they arose too soon to have involved a chain of transmission starting at the market. So the virus started elsewhere and the market merely sparked a cluster of infections. The rationale for closing these markets is still sound, even if those particular markets weren’t the origin of the current outbreak.

The first work out of China suggested that the virus came from bats via snakes. Why via? Bats are extraordinary critters. They can carry an enormous viral load without getting sick. Scientists are trying to work out how they do this, because it might help in the development of vaccines or medicines.

Of course, saying the virus comes from bats is a recipe for sparking vengeance on bats. It shouldn’t be. The locks on bat cells are very different to human cells, so very few viruses from bats can infect people and cause harm; and vaccines exist for those which can. As a bat rescuer, I’ve had these vaccines and also been bitten and scratched; I’m trusting them to work!

So for a person to be infected by a bat virus, that virus needs to acquire a large genetic change and the easiest way to do this is from a similar virus in another species.

It so happens that viruses similar to SARS-Cov-2 have been isolated from snakes. Hence the snake theory. It seems that most virologists don’t accept this, for the simple reason that gross similarity isn’t important. What matters is the part of the genome which generates the key… the bit which opens the human cell and allows entry. Which brings us to theory three.

Virus genomes have been isolated from Pangolins where the bit that generates the key is identical to the corresponding bit in SARS-Cov-2. It doesn’t much matter how similar the rest of the viral genome is, the Pangolins look to have provided the key… somehow.

Pangolins and pangolin meat are both illegally traded in many countries. They are part of the mumbo jumbo of traditional Chinese medicine (TCM). The Pangolin trade is illegal in China, with long prison terms if you get caught; but it continues anyway. Heavier jail time won’t fix this problem, what is required is cultural reform. Perhaps that can be driven merely by exhortations from famous people, but I think change can be deeper and more permanent if, in addition, everybody understands why the changes are needed.

Recombination, where different viral strains gain big chunks of genetic material from each other is known to happen in Corona viruses, but it’s not clear how. This is in contrast to flu viruses where it is common and well understood … mainly because the genetic material is in segments, in contrast to Corona viruses, where it is in a single piece.

Complicating the picture is research from 2013 where a virus was isolated from horseshoe bats (microbats, not the large fruit bats) which has a key which allows it into human cells. This virus isn’t SARS-Cov-2, but similar enough to ask why it isn’t causing similar havoc.

But what about the theory that this virus escaped from a research lab in China? That theory has been examined and it’s not plausible. People have modelled the kinds of key that would optimally bind to human locks and SARS-Cov-2 works differently… it’s a different key from the kind of key a lab would design, and it’s not built from the components that a lab would use… i.e. it doesn’t look like it was built in a lab but it looks exactly like it was built in a pangolin. It’s as different as pottery made in a factory is from pottery made by hand.

Bushmeat and cultural traditions

Hunting wildlife for food is as old as humanity. But the age of an activity has nothing to do with either its morality, sustainability or its propensity for helping diseases spill over from one species to another.

It is terrific to see a group of Chinese scientists writing recently in The Lancet, an esteemed western medical journal, and calling for a cultural transformation. “The ultimate solution” they write, “lies in changing people’s minds about what is delicious, trendy, prestigious, or healthy to eat.” Let’s hope the same message is echoed in the Chinese language journals and general media.

Globally, some 157 species of bats are hunted for food or because of traditional beliefs about some part of their body being good for treating some human ailment. People who hunt bats pose particular disease risks to the rest of us because of the unique physiology of bats.

Across China, in particular, farming of wildlife has become a massive industry. For thousands of years we have had domestic animals and hunting. Farming wildlife has never worked for many practical reasons. The Chinese have solved various practical problems and are now farming various species; without first domesticating them.

Pythons, cobras, turtles, forest frog, American bullfrog, coots, quail, peafowl, porcupines and more; these are all farmed, while some 5 million people work in the reptile farming industry.

Bats, on the other hand are still hunted rather than farmed. Their value to both us and the environment more generally is large – losing them would be like losing bees; simply unthinkable. Their pollination and seed dispersal activities are critical.

But bats have a capacity to carry viruses which makes messing with them particularly unwise. The dangerous inflammatory storm that our immune system can sometimes unleash – called a cytokine storm – seems absent in bats, which why they can carry a large load of viruses.

An individual handling bats is at a totally insignificant risk of infection, but millions of people hunting, slaughtering and eating bats makes wildly improbable events almost certain, given enough time. Add in multiple species and slaughtering and you ratchet up the risks significantly.

Eliminating bushmeat and wet markets is a massive challenge in areas of the planet without good stable food supplies or in areas where belief systems are judged on their age rather than on their impacts or validity.

Hopefully, the current global emergency will drive the kinds of developments that make bushmeat unnecessary.

The cultural beliefs surrounding meat eating will need to be dismantled concurrently. The threats of new diseases from intensive farming haven’t gone but perhaps will now be taken more seriously.