Why is it so hard to cure the common cold?

In 2000, a company called ViroPharma ran clinical trials of pleconaril, a new pill designed to treat the common cold. In many patients, the pill helped. But in 7 of them, just a few days into the treatment, researchers found mutated virus variants that were almost completely resistant to pleconaril. Viruses are always mutating, but this one mutated so quickly that it managed to outmaneuver years of research and development in just a few days.

If you didn't have an immune system and caught a cold, the infection would quickly spread deep into your lungs. Rampant viral replication would destroy tissue there until your lungs couldn’t supply your body with enough oxygen and you’d asphyxiate. Unfortunately, for millions of people around the world who live with a less-than-fully-functional immune system or who are on immunosuppressant drugs, this is a real risk: “minor” infections can turn serious or even deadly.

But if you're fortunate enough to have a fully functional immune system, a cold will probably give you a few relatively mild symptoms. On average, adults catch more than 150 colds throughout their lives. And despite the fact that the symptoms are similar, the cause could be different each time. Common colds are caused by at least 8 different families of virus, each of which can have its own species and subtypes.

How can so many different viruses cause the same illness? Well, viruses can only invade our bodies in a few ways: one is to come in on a breath. We have to breathe, so our immune system sets up a bunch of frontline defenses, and these are actually what produce many of the symptoms of a cold. Your mucus-y, dripping nose is your immune system trapping and flushing out the virus. Your fever is your immune system raising your body temperature to slow down viral replication. And your inflamed, well, everything—that’s your immune system widening your blood vessels and recruiting its white blood cell army to help kill the virus.

So, if the common cold is caused by many different viruses, is a cure even possible? Here’s one fact in our favor: a single family of viruses causes 30 to 50% of all colds: rhinovirus. If we could eliminate all rhinovirus infections, we’d be a long way towards curing the common cold. There are two main ways to fight a virus: vaccines and antiviral drugs.

The first attempt to create a rhinovirus vaccine was a success—but a short-lived one. In 1957, William Price vaccinated 50 kids with inactivated rhinovirus and gave 50 others a placebo. Soon afterward, a rhinovirus outbreak spread throughout the kids. In the vaccinated group, only 3 got sick. In the placebo group, 23 did—almost 8 times as many. And despite the small numbers, this was promising: the immune systems of vaccinated kids were successfully recognizing and responding to rhinovirus.

But later trials of the vaccine showed no protection at all—none. This wasn’t Price’s fault—no one at the time knew that rhinovirus had multiple subtypes. Price’s vaccine, for reasons we don’t fully understand, didn't provide broad protection, meaning it was only effective against one or maybe a few subtypes of rhinovirus—out of 169 subtypes and counting. Sometimes, when we make a vaccine, we get lucky. The mRNA COVID vaccines, for example, effectively protect us against severe disease and death across the original virus and variants too.

But we have yet to create a broadly protective vaccine against rhinovirus, or any other virus that causes the common cold. Okay, what about antiviral drugs? Viruses hijack human cellular machinery to replicate and spread, so it’s hard to make a molecule that’s toxic to the virus without also being toxic to the human. And even if you manage to do that, the virus could mutate out of reach of the drug. Viruses are slippery beasts.

We have, though, had some incredible successes: we eradicated smallpox thanks to an effective vaccine, the fact that it can’t hide out in other species, and its relatively low mutation rate. HIV, on the other hand, mutates so quickly that in an untreated individual, every possible single-letter mutation in the virus’s genetic code could, in theory, be produced in a single day. Despite trying for decades, we still don’t have a vaccine. But we do have an effective cocktail of HIV drugs that the virus can’t easily mutate away from.

Unfortunately, we are stuck with colds for now. But the last few decades have featured some entirely game-changing medical breakthroughs, like mRNA vaccines and CRISPR. CRISPR could be particularly promising as an antiviral agent because it originally evolved in bacteria as an immune defense against viruses. In fact, early in the COVID-19 pandemic, a research team showed that a CRISPR system could degrade coronavirus and influenza genomes in our lung cells.

They called their system prophylactic antiviral CRISPR in human cells. Or, for short, PAC-MAN.