Viral dark matter

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Last week on the show, we talked about phages, these viruses that kill bacteria and are kind of everywhere.

There's more phages in the human body than there are human cells, but we barely know anything about them.

So this week we wanted to share a favorite episode of ours from a while back, all about how these phages might be able to help us.

Reporter Nicola Twilley says they might be a great way to combat what's becoming a pretty major crisis, antibiotic resistance in 2016 the united nations pronounced antibiotic resistance the greatest and most urgent global risk the situation is bad and getting worse some scientists call it a slow motion tsunami and this isn't some sort of vague future threat already i think 700 000 people die each year because of drug-resistant infections.

That's predicted to rise to 10 million by 2050.

The world is heading towards a post-antibiotic era in which common infections will once again kill.

Surgeries that we might not think twice about are likely going to become more and more fatal.

Researchers have estimated that without any antibiotics, one in seven people undergoing just a routine hip replacement will die from a drug-resistant infection.

Doctors facing patients will have to say, I'm sorry, there's nothing I can do.

To make it worse, we did this to ourselves.

A lot of bacteria developed resistance to antibiotics because we overused them and we used them badly.

By feeding the piglets antibiotics milk, they are weaned away from the mother after three to six days.

We gave our chickens antibiotics.

A spoonful of antibiotic powder in a ton of food will increase the growth of chickens by 10%.

We threw it at everything.

People were given antibiotics for a, you know, stubbed toe, practically.

Some estimates say 50% of all antibiotics that are prescribed shouldn't be or are used inappropriately.

And of course, by doing that, we just increase the sort of pace of evolution, and bacteria are biological entities.

They're evolving.

Eventually, they figure out how to resist antibiotics.

But despite all this, there just might be some good news.

The big hope now is that we can take something that kills bajillions of bacteria every single day out in the wild and harness it for our own uses.

Those bacteria killers are called phages, and the potential here is enormous, but so is everything we don't know about them.

The scope of our ignorance is pretty epic.

They call it viral dark matter.

This is this completely unknown genetic code that only exists in the genomes of phages.

This viral dark matter could be the key to our future if we can just figure out how to use phages.

We know they exist.

We know that some of them kill the bacteria we want to see killed.

The only issue is we don't really know how to use them to do exactly what we want to do.

Okay, so Nicola, you wrote an article for the New Yorker recently all about this sort of vast, untapped medical potential of phages.

But before we get there, let's start super basic.

What exactly is a phage?

So a phage is a virus that attacks bacteria.

The full name is bacteriophage.

The phage part is from Greek, meaning to eat, and it's because they sort of eat the bacteria.

So bacteria are like us, they have to worry about viruses too?

Oh, yeah.

I mean, every sort of kingdom of life has its own complement of viruses.

So humans obviously get attacked by viruses, as we have seen with COVID-19.

Plants and animals have their own viruses.

And turns out bacteria do too.

They have phages, which are viruses that only attack bacteria.

What do they look like?

Oh, they are teeny, teeny tiny.

They're about 100 times smaller than the smallest things our eyes are physically capable of seeing.

So they are way smaller than even a bacteria, which is already at the edge of what we can see under under a microscope.

Okay.

So when you're seeing a phage, you're either seeing it through this kind of electron microscope, or you're seeing what it's done to bacteria.

So you're seeing like the clear patches on a petri dish where it's killed all the bacteria around it.

And what does it mean to attack bacteria?

How exactly does that happen?

When they find the right bacteria, they attach themselves to it,

they inject their genome into the bacteria,

and that genome is a set of instructions for making more little phage particles.

Sometimes they hijack the bacteria's own machinery to do that, sometimes they have little bits of machinery of their own, but basically they set about making more phage, and when there's enough phage, the bacterial cell explodes, and the phage go out and find more bacteria to infect.

Okay, so it kind of works like how the coronavirus works in our bodies, like making copies of itself and sort of destroying things along the way?

Yeah, viruses make copies of themselves and destroy things.

I think that's that's a great characterization of what viruses do.

And how many bacteria do they kill?

How often are they doing this?

They kill bacteria all day long and all night, too.

The estimate is that they kill half the bacteria in the world every 48 hours.

So they are really

efficient bacteria-killing machines.

Do we know how many phages there are?

No one knows exactly how many phages there are, but there are a lot.

One estimate says there are 10 million trillion trillion phages.

That's more than every other organism on Earth, including bacteria combined.

For every grain of sand in the world, there are a trillion phages.

And could bacteria evolve to resist phages like they did with antibiotics, or could phages kind of like evolve back?

Oh, yeah.

So that's another thing.

We would not run out of phages because they're just going to keep evolving too.

I mean, they have been locked in combat for millennia and they haven't run out of tricks.

So phages are always going to find a way to infect bacteria.

And so there will always be a fresh supply of phages that can attack any given bacteria.

Okay, so how exactly should we think about the medical potential of phages?

Well, so the idea is really, really simple.

The enemy of my enemy is my friend is the idea in a nutshell.

If you have a bacteria that is infecting you and causing you some kind of trouble, the idea is if you find the right phage that can, you know, attach itself to that bacteria and kill it, you would wipe out that bacteria.

Done.

So it's a really, really straightforward idea on that level.

Okay, and I imagine it is not so easy to do in practice.

Well, yeah.

Like everything in life.

So one thing to know about phages, which is both a strength and a weakness, is that phages are very, very specific.

A phage that will attack a particular kind of E.

coli bacteria will not touch a Staphylococcus bacteria.

What that means is you have to know exactly what bacteria is your issue and then find the right phage to attack it.

That already, that kind of matching mechanism is a step that makes it difficult.

So is this just a theoretical thing now?

Is anyone actually getting medical phages?

Well, so I met someone who has a drug-resistant bacterial infection.

His name is Joseph Bunavac.

He lives just north of Los Angeles.

He's 80 now.

He has gone through countless procedures, being opened up, sliced.

He's had half of his colon removed as doctors try to remove wherever the infection is sort of hanging out in his body.

But it flares up every, you know, few weeks, few months, and they infuse him with antibiotics enough to get the levels down again, but it doesn't kill the infection ever.

So it comes back.

I mean, his infectious disease specialist, she said to me, I can't believe he hasn't died a year ago.

I mean, it makes no sense that he's still alive.

What got him so sick?

No one knows.

That's part of the mystery of his condition.

Nothing is working, and so phage are the sort of emergency last resort.

And how would someone like Joseph get phages?

Is it a pill?

Is it a syringe?

Phages can be dosed in different ways depending on, you know, what the issue is.

In Joseph's case, he's getting them through an IV.

They're in solution in a little syringe, and they get injected into a port in his arm.

Oh, so he's gotten phages already?

He has.

So I first met him, I want to say in the fall of 2019.

It takes a long time to get phages for a variety of reasons that we can talk about, but he finally began phage therapy at the start of this year.

He's just finished his course, and I actually texted with Emily Blodgett, his infectious disease doctor, and she told me that at the moment, it looks really good but she needs a couple of weeks to be sure.

So is this kind of therapy still just small scale for now?

Well at the moment it's very limited.

It's only for these emergency use cases.

You can't just go to your doctor and get phages if you feel like you need them.

You have to be in an emergency where nothing else has worked and then your doctor has to file the paperwork.

Honestly, it's going to be complicated taking it beyond that because there's so much we don't know at the moment the FDA can't approve phages just as a medicine that's available to everybody.

Coming up after the break, turns out Hitler and Stalin are partially to blame for our lack of phage research.

Plus, how to go from hunting for phages in a river river to phages that can actually be used as medicine.

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I lit the fuse and my life turns into everything it wasn't supposed to be.

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He was the highest-paid TV star of all time.

When it started to change, it was quick.

He kept saying, No, no, no, I'm in the hospital now, but next week I'll be ready for the show.

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AKA Charlie Sheen, only on Netflix, September 10th.

A common cold?

No, no!

Okay, Niccolo, we're back.

Before the break, you were explaining how phages might just be this potential solution for antibiotic-resistant infections.

But you also said there's just so much we still don't know about them.

Is that the main reason we're still not at a point where lots of people can get phage therapy?

Well, the weird thing is, even though we've known about phages for more than a century, we have really only been researching them in the West as a therapy for the past

three, four, five years.

We're very behind in our research into phages as something that could treat infections in patients.

So when were phages discovered?

Well, so phages were first named in 1917.

They had been noticed a little earlier, but this is the first time that anyone was like, there's something, a phage, eating these bacteria and leaving dead zones.

So who first noticed this?

So it was a guy called Felix Darrell.

And he was a self-taught scientist and also sort of an outsider.

He appears to have had slightly of a difficult personality.

Okay.

Like a lot of sort of forward-thinking scientists, I guess.

Exactly.

Interesting character.

But he did discover these phages and immediately started sort of hyping the heck out of them like these were gonna cure everything.

Stalin was very interested in the potential of phages and invited Felix Durrell to come and set up a phage institute.

Because of that, and because the first photographs of phages were taken in the 30s in Germany, which was Nazi Germany, there was this sort of uh

lack of awareness of phages in the West.

And German and Soviet soldiers actually carried phages in their first aid kits during the Second World War.

Oh, wow.

I mean, people were using those.

Oh, yeah.

They would apply phages to wounds on the battlefield.

And then, after the Second World War, they became associated with Nazis and

communists.

Antibiotics were sort of fully established in the West.

And phages really fell by the wayside, except for in the Soviet Union.

It's like there was almost this fork in the road between antibiotics and phages, and the West chose antibiotics.

Is this sort of Nazi and Stalinist history the main reason phages fell off?

There's got to be more there, right?

Yeah, it's because phages are complicated and we like simple solutions.

After the Second World War in the West, antibiotics ruled.

For this type of blood poisoning, penicillin is a sure weapon.

They seemed magical.

You won't need to worry.

We'll have her out of here in a week.

And the thing about antibiotics that makes them so attractive is that they kill all kinds of bacteria.

Give her this antibiotic five times a day.

I think you're going to be all right, Kathy.

The way I think about antibiotics is they're like a hammer and your infection is like a nail and the hammer just works.

It does the job.

You don't have to understand even what particular infection you have.

You just hit the nail with a hammer, job done.

You don't go through this entire complex process of finding the right phage for these bacteria.

I mean, phages and bacteria are the ones with the ecosystem relationship, and we're trying to kind of choreograph that relationship, and we don't know what we're doing.

So if phages are these wild things we need to figure out how to choreograph, where do you find them?

Well, so they're everywhere.

You can get them from everywhere.

But if if you want a phage that will kill the kind of bacteria that is usually a problem for folks,

really where you want to go hunting for phages is in

gross places.

Okay.

So

what kind of places?

Well, so I got to go on a phage hunt.

I bought a new pair of

rubber boots.

In Southern California, where I live, the best time to phage hunt is after rainfall because the water system will have become overwhelmed and the sewage will have just been kind of pumped out directly.

You find your patch of murky-looking water, you grab a little test tube and get a sample of that water, and then you take it back to the lab.

And what do you do once you're back in the lab?

If you just want to know what's in there, you're just gonna sequence the DNA.

If you want to see if you have a phage that is going to be useful, killing a particular bacteria, then what you do is you get that bacteria, you put it on a Petri dish, and then you drop little bits of your purified phage on there, and you wait and see what happens.

And you're basically testing to see if the phage will be able to kill that particular bacterium.

Yeah, if you're successful, you'll come back and there will be sort of these spots of clear patches where there's no bacteria living anymore.

Okay, so we got this association with Nazi Germany and the Soviet Union that maybe set back the research.

We've also got the fact that phages are super complicated and nothing like this hammer and nail model we have with antibiotics.

Are there other downsides here?

Like, can phages be dangerous?

Yes.

A lot of phages just go in and start making copies of themselves, but some phages go in and just hang out and insert their DNA into the bacterial DNA.

Those kind of phages...

They're responsible for making the cholera bacteria into something that kills humans.

The phages go in, give the cholera bacteria what is called virulence.

So they're not our friends.

They're just the enemies of our enemies.

And the enemies of our enemies, I guess, can easily be our enemies too.

Yeah, they can.

I mean, there are a lot of unanswered questions.

And when there are a lot of unanswered questions, the chances that we could do some accidental harm are high.

Okay, so now that we know all of these things standing in the way of widely accessible phage therapy and there's a lot of them, do you think this is in our near-term future at all, going to the doctor and getting phages?

I think increasingly in the near term, they will be available for emergency cases

because

we are running out of other options.

There's a lot of research that needs to happen, but the idea that they're going to replace antibiotics for most of us or that they'll be available for most of us in the near term, I think is wishful thinking.

I think it's going to be a decade at least.

And if this is still kind of a long-term goal here, I assume there must be other benefits we could get from,

I guess, expanding our research priorities, right?

I mean, you called it viral dark matter at the top.

I imagine there could be lots of other reasons to research this beyond medicine, right?

Yeah.

Even if this doesn't turn into a therapy that's available for everyone in the, you know, in the next five years, we really need to do this research.

One, because antibiotic resistance is a huge crisis.

And so let's build the tools we need now before we run out of antibiotics.

And two, because phages are like the puppet masters that are shaping the bacteria all around us, and the bacteria all around us are shaping the environment all around us, our health, the health of the soil.

the health of the plants and animals all around us.

And so it's a key to understanding how the entire biological ecosystem works.

If we had a handle on what they were actually doing and were able to press some levers and understand how phages would respond, we'd be able to do amazing things.

So the research is worth doing.

There's going to be gold in there.

Nicola Twilley is the the host of Gastropod, a podcast examining food through the lens of science and history.

She wrote about phages for the New Yorker, and she's got a new book out right now.

It's called Frostbite, and it's about the impact refrigeration has had on everything from farms to global economics to our health.

Since we originally aired this episode in 2021, phages still haven't become available to use for most people, but they are being used in the food system.

Gastropod's got a great episode called Phage Against the Machine, if you want to learn more about that.

Also, we reached out to Emily Blodgett, the doctor who treated Joseph with phages.

And as of a few months ago, so several years after he initially got this treatment, he was doing fine.

So way to go, phages.

This episode was produced by me, Noam Hasenfeld.

We had editing from Jillian Weinberger, Brian Resnick, and Meredith Hodenot, who runs our team.

Mixing and sound design from Christian Ayala, music from me, production support from Bird Pinkerton, and fact-checking from Manding Wen.

If you have questions about this episode or thoughts, please send them to us.

We're at unexplainable at Vox.com.

You can also support this show and all of Vox's journalism by joining our membership program today.

Go to vox.com/slash members to sign up, or you can always support the show by leaving us a nice rating or review.

Unexplainable is part of the Vox Media Podcast Network, and we'll be back next week.

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