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Do Bad Viruses Always Become Good Guys in the End?

We are often told that viruses always evolve to become benign. In reality, virulence is a double-edged sword.

In our social media age, talk of virulence has gone viral, with most of us atwitter about the course the new coronavirus is taking. As novel variants move up the ladder of concern, we are left asking the same questions: is this one more transmissible? is it more dangerous to us? will our vaccines stop it?

There is a seductive undercurrent to these discussions, a bit of common wisdom, we are told. Viruses apparently always evolve to become less lethal over time. Like wolves domesticated into dogs, disease-causing viruses seem to become tamer in an effort to survive. The reasoning goes that, sooner or later, SARS-CoV-2 must lose its fangs and become as boring as the common cold.

It may seem cruel to snatch one of the few hopeful mantras we still have in this incessant pandemic, but the record must be corrected. The idea that disease-causing organisms always become benign—a hypothesis known as the avirulence theory—was debunked.

While the story may be “hare raising,” it also involves bunnies.

Kill the wabbit

The year is 1859. Charles Dickens’ A Tale of Two Cities is first published as a series of weekly installments. Charles Darwin publishes his famous book, On the Origin of Species. And European rabbits are introduced to Australia so that they can be hunted.

This was the doing of a wealthy settler by the name of Thomas Austin, who had thirteen rabbits brought in, which he let roam about freely on his land. Cut to fifty years later: rabbits have spread all over Australia, harming native species and crops. You could say they bred like rabbits.

A mere twenty-eight years after their introduction to the land down under, they had proven to be such a pest that the Australian government was offering a prize to anyone who could control the growth of their population. One suggestion was to use a lethal virus.

It was called the myxoma virus and it was chosen because it was thought to specifically affect rabbits. Many attempts were made to import the virus and unleash it into the rabbit population. By the early 1950s, it was a success. The virus was deadly 99.8% of the time. A subsequent outbreak of the virus in rabbits, however, only had a mortality of about 90%. Basically, the virus, first coming into contact with its hoppity host, had been very virulent, but over time, its virulence had decreased. This lent support to a theory that had been proposed as early as 1904: that viruses necessarily become less virulent over time.

Generally speaking, virulence means the harm or the reduced fitness that a disease-causing organism, like a virus, inflicts upon its host. The avirulence theory, backed up by the Australian rabbit experience, made sense. If a virus kills its host instantly and consistently, the host will not be able to spread the virus to someone else. The virus will, in effect, “die” with its host in what has been referred to as a pyrrhic victory. From an evolutionary standpoint, it is far from advantageous. It is, in fact, a dead end. Evolving to be less virulent sounds like a better bet.

It is important to point out, though, that there is no intelligence behind evolution, nor are viruses capable of thought. They are mere bundles of genetic instructions which call for their own duplication, a process that, like typing in a handwritten letter, lends itself to typos, i.e. mutations. It is thus hazardous to think of any virus as having a will to survive and of thus wanting for its host to cling to life long enough to help spread the little bugger. The avirulence theory beguiles our desire to anthropomorphize the billions and billions of viruses on our planet.

But in truth, there is no grand design; instead, there are forces that act on both viruses and hosts. Our scientific understanding eventually moved beyond the avirulence theory and into a more nuanced thinking: that it was all about trade-offs.

It’s always more complicated than it looks

Tuberculosis has been with us for hundreds of years and it is still deadly. Dengue fever’s own virulence has risen over the last decades. And the myxoma virus, slayer of rabbits? It too has grown deadlier fangs, according to limited data from the 1980s, with a larger percentage of circulating virus in Australia being highly virulent compared to the previous decade. The universality of avirulence theory simply has too many contradictions. Viruses don’t always evolve to become benign.

Mathematics played a big role in bringing a more refined understanding to the interplay between viruses and their hosts, allowing for more precise models to be crafted and tested. As always, it turned out to be a lot more complicated than first imagined. Now there’s a slogan for the scientifically minded.

Let’s explore a few scenarios that show this complexity by transplanting our brains into viruses and seeing the world from their perspective. Imagine we are the rabies virus. Do we need to evolve to be benign in humans to survive in the long run? No, and clearly we haven’t. Once symptoms appear, rabies is essentially 100% fatal in humans. And that’s OK, because we can survive and spread more easily in an animal host, like dogs, bats, and raccoons.

If we are SARS-CoV-2, the virus responsible for COVID-19, and we are spreading in areas where lots of people congregate indoors, the cost of killing our host is much smaller than if we attempted to spread in a place where few people lived, because transmission would be harder. So we can get away with being more virulent in high-density areas and we will still get around.

Finally, virulence is not just about lethality; it’s also about harming the host. As SARS-CoV-2, we can afford to be virulent and thus make recovery slow. The longer we stay in a host, the more copies of ourselves we can make, and the more opportunities our host has to spread us around to other hosts. If we look at virulence through this lens, there are both costs and benefits to being a bad virus. It’s all about trade-offs.

In fact, when a virus sticks around a person for weeks, it has more time to mutate. This can happen if the host is immunocompromised, for example. The virus is allowed to linger and thus make more and more typos in its code. Even though the virus is not aware of it (because it lacks a brain), what it does is akin to gambling. If you play at a single roulette table, your odds of winning are small. But if you place bets at 50 different roulette tables, the odds go up. The more copies you make of yourself, the more mutations will occur, and the higher the chance that one or several of these will pay off.

This is one of the hypotheses—and I must emphasize, hypotheses—behind the emergence of the Omicron variant of the coronavirus: that maybe the virus stuck around for a while inside someone whose immune system was compromised, and thus accumulated a string of typos that, by chance, gave it an advantage. And thus Omicron was born.

A swarm of mutants

The ability for genetic material to change—to mutate—and thus potentially alter what it codes for to improve its fitness to its environment is at the core of evolution. Mutations can be silent, meaning that they do not change the protein they code for because of redundancies in the code. Mutations can be bad (think of mutations predisposing someone to cancer, like certain BRCA1 and BRCA2 mutations). But once in a while, a mutation can be beneficial. And viruses are in a great position to play the odds.

An infected person can produce one thousand million infectious viral particles during a single bout of infection. As Dr. Jonathan Yewdell of the National Institute of Allergy and Infectious Diseases recently wrote for the journal Immunity, for viruses that mutate rapidly this means a “swarm [including] viruses with mutations at each position in the genome” coming out of a single infected individual. That is an impressive degree of genetic diversity.

If these mutations affect how the virus interacts with our immune system—such as the shape of the coronavirus’ spike protein—this change from the original virus to a new version of the virus is known as antigenic drift. And if two different viruses are present in the same cell and pieces from them get accidentally sewn together, à la Frankenstein’s creature, we get antigenic shift. The pandemic influenza strains we have had to weather in the past, like 2009’s H1N1, were likely due to this rare kind of antigenic shift in an animal; but the variants of SARS-CoV-2 we have to put up with now, those arise through the more common antigenic drift. And multiple pressures work on these variants to test their fitness in the human bodies in which they can thrive.

In a publication on why parasites harm their host, Pierre-Olivier Méthot, then post-doctoral fellow in Europe, now professor here in Quebec, wrote a beautifully pithy sentence toward the end: “The conquest of equilibrium is always precarious.” Viruses mutate. Hosts adapt. Some viruses become less virulent while others gain a nastier edge. Humans develop vaccines. Viruses drift and shift. Scientists revamp their vaccines. It’s a biological arms race.

The avirulence theory made predicting the future simple but wrong. If this pandemic has taught us anything, it is to remain on our toes. As the virus adapts, so must we.

Take-home message:
-The idea that viruses always evolve to become less lethal because it is advantageous to them is an old theory that has been shown to be wrong
-Viruses can become more or less virulent over time-based on a number of pressures that act upon them
-Viruses can develop random mutations that happen to affect how they are recognized by our immune system (antigenic drift) and, more rarely, pieces of their genetic code can get recombined with the genetic code of another virus to create a brand-new virus (antigenic shift)


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