• Alex Cloherty

Hammering SARS

When Thor saw the hammer his heart laughed within him, and he took courage. He first slew Thrym, the lord of giants, then he crushed all the giant's kin. Finally he slew the old giantess who had begged for a bridal gift. Instead of coins she got the crack of the hammer. Instead of rings she received the mark of Mjöllnir.

Imagine this scene, but with Thor as scientists, the giants as the SARS-CoV-2 coronavirus, and Mjollnir, Thor's hammer, as the latest drug against COVID-19. And there you have it: a Nordic (or Marvel)-inspired take on current events.

This new anti-COVID-19 drug in question is in fact it is named after that very hammer of Thor. It's name, molnupiravir, is perhaps a bit longer and harder to pronounce than Thor's Mjollnir, but it is nonetheless a name that you have likely seen in the news over the last few days. On Friday, October 1st, 2021, Merck announced the first promising outcomes from the ongoing phase 3 clinical trials with this molnupiravir. It was safe, it could be given orally, and it prevented COVID-19 deaths.

So, we have a new option for treatment. The next question is, how does it work? The short answer: forcing the virus to mutate.

Now, as a fan of microbiology, you might have read that and thought, "What? I thought that we didn't want the virus to mutate, because that could lead to the evolution of new viral variants of concern." That is exactly the question that a very smart friend of mine asked, and which inspired this week's dive into microbiology. So, let's get into it.

The mechanism of action behind molnupiravir, and behind other drugs that use its same strategy, such as already available anticancer, antiviral, antibacterial, and immunomodulator drugs, actually starts with a question: how much can something mutate, before it can no longer survive?

Mutations are interesting, because they are happening all the time, but in a totally random way. Any living thing on the face of the earth can mutate at any moment, and it is a total throw of the dice in terms of whether that mutation might benefit the living being in question, be detrimental, or have no effect at all. But where it gets really interesting, is if we look at mutations that can be passed on to progeny - that mutating living thing's kids.

To unwrap this concept, let's look at the case of the peppered moths of the United Kingdom. Famously, these moths had a distinctive black-and-white, salt-and-pepper colouring prior to the industrial revolution. This allowed them to blend in with the speckled birch tree bark in their habitat, avoiding predators. However, as the soot of industry steadily blackened the trees of the nation, these salt-and-pepper moths became distinctively purely peppered: over the years following 1819, they turned black.

This intriguing story is commonly explained as follows: The trees turned black, so the moths also turned black. However, this interpretation is overly simplified, and in fact incorrect. The ways of nature are far more mysterious - and random.

Throughout the history of the moths prior to the 19th century, many of their compatriots had likely been born fully pepper-coloured due to random mutations in the eggs or sperm of their parents. Note that two salt-and-pepper moth parents could thereby have given birth to a pepper-only moth baby. Parents don't necessarily have to look like they have a mutation in order to pass it on to their kids. That is because mutations are typically due to random events like so-called editing errors in copying genetic material. For example, as egg and sperm cells divide, you can think of it like a typist having to re-write the same ten-thousand word essay over and over again... And on a typewriter. There will likely be some typos, and those typos will likely not occur in the exact same place in every copy of the essay. In other words, if a mutation only occurs in the egg or sperm cell of a parent, the rest of the parents' cells won't have that particular mutation - but it can be passed on to the child that results from that egg or sperm.

So, let's say that a pepper-only moth baby is born in the 1700s. It has this mutation that changes its colouring, and it can even pass on that mutation to its own moth babies if it has any. However, in a world with little soot, that pepper-only moth baby is rather unlikely to have any moth babies of its own, because it doesn't blend into its environment. Against the off-white birch bark, that pitch-black moth baby is an easy target for predators. Thus, pepper-only moth babies will be born, just as salt-only moth babies may be born, but they will quickly be eliminated from the moth population because they are not only a tasty treat, but a very visible treat for the birds that hunt them.

In short, in a soot-free world, most of the reproducing peppered moth population will be salt-and-pepper moths, because the dice are weighted towards the survival of moths with their colouring. But again, this doesn't mean that pepper-only or salt-only moths will not be born - only that 1) a random mutation in the eggs or sperm of their parents would have to happen to cause their colouring to differ from that of their ancestors, and 2) if they are born, they will likely not survive to adulthood, nor reproduce.

But then, in the 19th century, the rules of the game changed. With the coming of the soot of industry, suddenly it was the salt-and-pepper moths that were easily being picked off by birds, instead of the pepper-only moths. Relatively quickly, the tables turned and the pepper-only moths gained an advantage in surviving and reproducing. And indeed, they made lots of little pepper-only moth babies. Within about 50 years, the pepper-only moths were in the vast majority.

But then, only about a century later, the rules changed again. With the introduction of clean air laws in the mid-1900s, suddenly, there was less soot on the trees, and as a result the salt-and-pepper moths regained some advantage.

Now, all of this is to say that depending on the current situation, a given mutation can be beneficial, or it can be detrimental. Whether or not the mutation helps, or if it even happens, is rather random, and if the rules of the game change, the outcome of the mutation can change, too. In short, there is no grand scheme behind mutations. They just happen.

The same rule of randomness is true with viruses. As with all living things, viruses are constantly mutating. Sometimes that mutation is helpful for a virus, and can help it better hide from immune systems. Sometimes that mutation means that the particular virus that acquires it is defective, and it can no longer even infect its target cells anymore. And sometimes, that mutation has no effect at all and the virus goes along on its merry way with no idea that anything differentiates its genetic code from that of its parents.

So, let's get back to molnupiravir. If introducing mutations into a virus is such a random throw of the dice, why would we want to take that risk?

The key is the amount of mutations that are introduced simultaneously. And for that, we will return to Thor and his hammer, Mjollnir.

You can think of molnupiravir exactly as its eponymous Mjollnir, and each mutation introduced by it as being a hit with that same hammer. When Thor delivers a first blow to a powerful enemy, it may dispatch that enemy in one fell swoop, or it may only serve to notify the enemy of Thor's presence, make him or her increasingly angry, and level up the battle. That would be analogous to hitting SARS-CoV-2 with only one mutation: it could just as well knock out the virus (good), or make it more powerful (bad). It's a throw of the dice.

However, the power of molnupiravir is that it doesn't only introduce one mutation at a time: it hits the virus with a volley of mutations, rendering it unrecognizable from its previous form. This would be analogous to Thor hitting some distasteful giant rapid-fire until said giant is little more than a giant pile of goop. A sufficient dose of molnupiravir hits SARS-CoV-2 with so many mutations all at once, that it is nothing but a limp, barely recognizable fragment of its former self. It becomes a sort of lethargic, flightless, easily visible moth that can be easily picked off by the human immune system.

Now, as much as I acknowledge and respect Thor and his Mjollnir, I also learned recently that Captain Marvel is most likely more powerful than Thor. Likewise, there is also a more powerful option than molnupiravir against COVID-19: any of the freely available vaccines. I am definitely happy that we have another drug available that can protect people from severe effects of COVID-19, including death, but let's face the facts. This drug doesn't protect against infection with SARS-CoV-2 (unless perhaps you were to take it 24/7, which is not the form of administration that it's been tested for), and it doesn't protect against hospitalization and death to the same extent as the available RNA vaccines do. As Thor is to Captain Marvel, molnupiravir is impressive, but essentially a weaker hitter than the RNA vaccines.

So to end, I'm definitely not saying that Thor's not a cool dude - but I am saying that I have a preference for Captain Marvel.

Until next time,

… Carol Danvers, ahem, the vaccine, still wins.

~ Alex

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