This is staphylococcus bacteria, or ‘staph’ for short, and bacteria probably immediately makes you think of illness, infection and disease.

There are bacteria all over and inside of our bodies.

They're a natural part of us.

They're an essential part of being human.

We literally wouldn't be alive without them.

Now, even though the vast majority of bacteria mean you no harm and are actually on your side, if they get somewhere they're not supposed to be, it can mean trouble, like an infection.

And I think we’ve probably all heard of the solution, which is antibiotics, a medicine we take for granted these days.

But would you believe that antibiotics were actually discovered completely by accident?

And that's what I'm trying to do here.

I'm trying to replicate this world- changing accidental discovery stumbled upon by a man named Alexander Fleming in 1928.

So let's see what grows.

Quick question, I'm so sorry.

- Do I look?

Where do I look?

- Anywhere you want.

Literally anywhere you want.

But it's okay if I just stare into your beautiful ..

Certainly.

Perfect, okay.

My handy dandy little mini incubator!

Just normal things that people have.

Okay, I am not entirely confident that this actually was the way ..

So let's see, shall we?

Okay.

Yeah.

No, absolutely nothing grew.

Oh, that's such a shame!

Do you mean it was a fascinating fail?

Well, it was certainly a failure!

Okay cool!

Luckily, I have extra plates.

- Would you like a swab?

- I would love a swab.

Okay.

What am I going to swab?

I think I might do my mouth.

What are you gonna do?

I want to do the corner of my eye.

Is there any bacteria in there?

- I would hope!

- We'll see.

The story of how Fleming made his accidental discovery usually goes something like this.

He left some plates of bacteria out on a lab bench.

He left a window open, went off on vacation.

He comes back from vacation and his plates are covered in mold.

But he notices that in the area around the mold, there are no bacteria growing.

So he says, ‘huh, this fungus must have some kind of bactericidal effect.’ and ta da!

We have antibiotics.

But really, there's a little more to it than that.

There's kind of some debate in like the historical circles, because there's no contemporaneous account of this.

He basically comes up with this story months after he does like his first official experiment.

It's a retroactive origin story.

Maybe, potentially.

There's no doubt that he did, like, accidentally.. Yeah.

It's jus.. basically, like as a microbiologist, no microbiologist worth their salt - is going to leave that window open.

- RIght!

And also the street is really busy.

And they were like you couldn't hear yourself think if you left that window open and comically, they're like, Fleming was really short, - and that window was really high.

- Ooh!

- The detectives!

Getting in on the details!

- Yes!

Literally!

It’s crazy, they even look back at the weather data from the time and they were like there were only two days That It could have even, like, grown, because it was too cold, unseasonably cold for that time of year!

It was like really real detective work.

Okay, so people have really, like - thoroughly debunked that.

- Really dug into this.

Now, whether Fleming jazzed up his origin story or not, we'll probably never know.

But what he was noticing looked a little so.. And yes, this is the bacteria from inside of my mouth.

Blech, I know, but it's a good thing.

there are supposed to be bacteria in there.

What I added was an environmental fungi that I found on some moldy fruit in my refrigerator.

Don't judge me.

And what we can see here is this zone around the fungus where there is no bacteria growing anymore.

We call this the ‘zone of clearance’ or the ‘zone of inhibition.’ Now, this happens in nature because fungi and bacteria are often occupying the same niche, which means they're competing for resources like food and space.

So many fungi and other microorganisms have evolved to produce antibacterial, or bacteria- killing, compounds to sort of edge them out of the territory, gain an advantage.

And when Fleming notices this happening in his petri dish, he wants to know more.

He asks his upstairs or downstairs neighbor to identify the fungus.

It's wrong.

They misidentify it, and that does not go noticed for the next two years.

- Oh my God.

- Yep.

Not great.

But then he does like a series of kind of experiments to understand it more.

He learns how to grow it, but he can't make it stable and he can't isolate the pure substance itself, what he termed ‘mold juice’ initially.

He can’t isolate it from that growing broth, which means that they can't actually use it therapeutically, because if like I injected that into you, you’d die.

You’d just have anaphylactic shock and die.

You can’t inject straight up mold into somebody, but you would want to take that bactericidal compound out of the mold juice to then purify and use it as a medicine.

And he's like, totally incapable of doing that.

Yes, because he's not a chemist.

- Yeah.

- That’d be so heartbreaking— [doorbell rings] You know what else is hear..

When someone rings your doorbell in the middle of filming!

Anyway...

It all comes back to the question of why was Fleming so interested in discovering what this was?

Why would it have been so important?

Well, I feel like to understand that, you kind of have to go back to what Fleming did before.

He was sent to the Western Front in France and he was a bacteriologist.

And he witnessed soldier after soldier come in with these horrend.. from the battlefields, just filled with mud and poop, and then he just watched them get sick and die, and there was nothing that they could do about it.

And so he became really interested in wound infections and how to fix that, because basically at the time, antiseptics, like what you would use in surgery to, before you cut, that was used in wounds, - but that could— yep.

- Just like straight up?

Just straight up soaked a rag into it and then packed it in.

Right, which like, yes, may kill some bacteria but will also just like hugely damage your tissue.

- Exactly!

- And all of your immune factors.

And it pushed bacteria further into the wound.

So when you think about like what a war wound is like.

It’s jagged.

It’s deep in there.

And he figured out that actually you needed something that wasn't surface level, that wasn't something that you could rub on, that it was systemic.

That was probably what they were going to need to try and help with these infections.

So Fleming recognizes that this could be a pretty huge deal.

He knows that this thing that he's noticed in a petri dish could save lives if he could just get it to work without the fungus part.

He named his discovery penicillin after the Penicillium fungus that creates that antibiotic activity and he tries experiment after experiment after experiment to isolate the actual antibiotic compound in that mold juice.

But he can't do it and he gives up and publishes his last thing on penicillin in 1932.

He does, however, send out samples of his accidentally-discovered mold like this one here, in the hopes that somebody else might be able to purify it.

Which is how it comes to be picked up again nearly eight years later, here at Oxford University, by Howard Flor.. Ernst Chain and Norman Heatley, who decide to be big nerds about it.

And I do mean that literally.

They did not pick up on Fleming's penicillin work because they thought it could save lives, they literally just found it academically interesting.

But that all changes when they're finally able to actually isolate the antibiotic compound from the mold juice, Here at the Dunn School of Pathology.

They test it in mice and it works really well.

‘And Professor Florey declared it looks like a miracle!’ [choir: Awesome!]

So, it’s official!

Penicillin works against bacterial infections in mammals.

And Germany is now at war with England.

So it's becoming clear that something like this would be really useful in preventing the kind of wartime casualties that were so catastrophic during World War I.

And now the mold juice factory begins in earnest.

The Oxford group also included six women.

This is the only photograph I've ever been able to find of just two of them.

And they worked around the clock to cultivate the mold and isolate the active compound and filter it so that the group could use it for their research.

Because, as it turns out, the original mold that Fleming accidentally discovered just didn't produce a lot of actual penicillin.

They were using bathtubs, bedpans, biscuit tins, pretty much anything they could get their hands on that they could grow mold in.

To truly emphasize just how much mold we’re talking about needing here, I have to tell you about the first person who was ever treated with penicillin, right here at the Radcliffe Infirmary.

His name was Albert Alexander.

Legend has had it that he scratched himself on a rosebush while gardening, but we now know he was actually injured in an air raid.

And from that injury, he develops a really nasty bacterial infection.

In the words of Heatley, he was oozing pus everywhere.

It takes 2000 liters of mold juice to produce enough penicillin to treat just this one man.

But, it does start to work!

He starts to get better.

But unfortunately, the team A) doesn't know how much they need to give him in order to totally clear his infection.

and B, they don't have enough of it anyway.

So, unfortunately, Mr. Alexander does go on to die of his infection, and even though now the team knows it works in humans, they really need to scale up their production.

Enter the USA.

Heatley and Florey bring their fungus— which, at this point in th.. is now considered a matter of national security— secretively across the ocean to Peoria, Illinois, where they share what they know so far and attempt to scale up the production of penicillin, and where scientists decide they need to conduct a good old-fashioned treasure hunt— for moldy fruit!

They're searching for a strain of Penicillium fungus that produces more penicillin than Fleming's original stingy strain.

And they find it!

Thanks to Mary Hunt, a lab assistant whose nickname bec.. because after much searching, she's the one who finds a rotting cantaloupe at the local farmer's market that's covered in a Penicillium fungus that produces six times more penicillin than the original strain.

The team finds that if they irradiate the mold with X-rays, it produces even more penicillin.

And fun fact this mutant strain of cantaloupe .. for most of the penicillin produced in the world today.

With this more productive mold and lots of improved manufacturing practices, penicillin production scaled up to 100 billion units by D-Day in 1944, enough to treat every single Allied soldier and civilian wounded in World War II.

The discovery and success of penicillin set off this golden age of antibiotics, Where from 1950 to 1970, scientists discovered about half of all of the classes of antibiotics we still use today.

In the United States and many other places around the world, the leading cause of death changed from infectious diseases to noninfectious causes, things like heart disease and cancer.

Since its initial discovery and its synthesis into an actual therapeutic drug, it's estimated that penicillin has probably saved over 500 million lives.

That's over half a billion people.

So everything is great, right?

We finally have a way to combat the previously deadly and unstoppable foe of bacteria.

We're basically invincible.

Antimicrobial resistance.

- Wait, what was that sound?

- Antimicrobial resi.. Well, basically, as soon as we discover antibiotics, we also discover antibiotic resistance, which we now today call antimicrobial resistance.

Because remember how I said earlier that fungi and other microbes are what have evolved to produce antibiotics in the first place.

Well, bacteria have evolved back— basically their own weapons and battle armor that keep those antibiotics from being able to kill them.

And because bacteria multiply so freakin’ fast, they're able to have developed these mechanisms in a relatively short span of time.

And the more we use antibiotics, the more we see bacteria developing these resistance mechanis.. Like, if nothing is done about this, scientists estimate that by 2050, up to 10 million people a year could die from antibiotic-resistant infections.

Just think about that.

Like you have an infection and you're in the hospital, and we just a couple of years ago had an antibiotic that could treat it, but now there's nothing we can do?

Everything from routine surgeries, to cancer treatment, to childbirth have become so much safer because of antibiotics.

So to feel this backslide into the past?

Pretty freaky.

But luckily, science is on the ca.. And this is where I need you to pay special attention to my earrings.

This is a bacterium, and this...

This is a phage.

A phage is a virus that can infect bacteria.

Oh my God, I can't believe we actually can see it!

So there are viruses that can make you unwell, when you get the flu.

But there are also viruses that can help us.

And that's what a phage is, because It only infects bacteria.

Whoa.

Okay, so they're like bacteria’ natural predators.

Like heat seeking killers for bacteria.

So you've got the nice head and the long tail.

When it actually infects, you can see it's actually kind shriveled up really nicely.

Right, it’s like squinched.

And what you're seeing here is lik.. And so what that will do is then inject the DNA into the bacteria cell— Holy schmoly.

And then it hijacks the bacterial cell to make many, many, many copies of itself, which eventually kills the bacterial cell and then perpetuates the phage.

What an efficient system!

So if you know that there's this bad bacteria causing an infection, then you can go, right, I am going to find a phage for that, and I'm going to use that phage to kill it.

Bacteria and viruses, which is bacteriophage, have been in a war for as long as they’ve both existed.

It's something that is, I would say, an old technology.

Actually, phages were found to treat bacterial infections before antibiotics.

But it kind of out of fashion.

And so we just went, we’ll run down the antibiotic route.

But obviously now we're coming back to the bit where we go, oh actually, antibiotic resistance, maybe we do need to go back and look at this technology that we've had for hundreds of years.

That's incredible.

So phages are like this vintage thing.

They're like, ‘look who came crawling back after antimicrobial resistance, - You need me!’ - Exactly.

They look like a machine, the look like they’ve been built.

The amazing thing is actually they auto-b..

So you imagine all these bits of protein are made in the cell and then they just know to assemble in a certain way.

That’s at the top, that goes there, that goes there, put some bits on the end, go.

It's the IKEA flatpack of the microbial world.

That’s the one!

So now we've seen some photos of them, do you want to see how we work with them in the lab?

Yes, please!

I'm going to show you today how we assess if phages work against a particular bacteria.

So we're just going to grab some of the phages.

Let's pick one of my favorite ones today.

We’ve got our plates, we’ve got our bacteria.

So we need a nice soft agar surface and we need the bacteria to be grown all the way through it to make a nice lawn.

A lawn of bacteria... a bacterial lawn!

And then that's the way that we can see when the phages are killing the bacteria.

And, Mel, these are the phages that we saw under the microscope, that's them in the tube, and we saw them!

How many would you say are in that tube?

There would most likely be billions in there, or hundreds of billions, but that's what we kind of have, these kind of levels - That's wild.

- So they’re in every drop.

And then we wait overnight.

But, here's one we did earlier.

You can see, it's all really nice and cloudy in the background and that's where you've got your nice bacteria lawn.

And then what you can see is, where the phages have worked, you get that nice clear area where there's no bacteria that’s grown.

So you can see in a number of different areas on this plate.

And then what you'll say is that phage has worked, that phage can kill that bacteria.

- That's so cool - And that’s what we're looking for.

The main thing that we need to take away from this is phages are everywhere.

Anywhere that bacteria are found and growing, that is where you can find a phage.

So one of the fun places that we do and sometimes the lab does smell a little bit, I won’t lie, is that if you go and find sewagewater, i.e., stuff that you flushed down the toilet, that is an excellent place to find phages, For us, the main thing that we're trying to do, so I am a doctor, and I'm interested in treating infections that are really difficult to treat in the community.

Now, one of the biggest ones that we have is for urinary tract infections, so that's if you have an infection anywhere from your kidney to your bladder, and the top two organisms that cause problems and are difficult to treat are E.coli and Klebsiella, which make up between 75 to 81% of all UTIs.

And so the problem we have in the hospital, and when we're treating from our doctor side is that antibiotic resistance is really coming into play now.

And these bacteria aren't just developing increasing antibiotic resistance.

They also form something called a biofilm.

This is where the bacteria produce all these ooey gooey factors that you can see on the plate here, and those help them stick to each other and stick to surfaces, like the lining of your urethra.

And just imagine, now we have antimicrobially-resistant bacteria forming biofilms inside of our urethras.

Whoof!

Now, what's really cool about phages, and another thing that is really close to my heart and makes me excited, is the fact that phages can destroy biofilm, and therefore then offer these patients a way to be treated and finally get rid of these long-standing infections that keep coming back time and time again.

I imagine we have more sophisticated or more true to life ways to study biofilms and the phages’ effect on them than like just a petri dish.

So what are we using?

Karen Adler, which is one of my PhD stud.. has very lovingly curated this with a labor of love.

it's lovingly called the Artificial Bladder.

So what we did is, I went to the local urology ward.

And every time people who had long-term catheters, they just come to the clinic every about 8 to 10 weeks and they have their catheter changed.

So I collected them and I built this system to sort of house these catheters.

So you start here with— it's bacteria food that we made by a recipe to sort of mimic pee.

- Fake pee!

- Fun!

- And inside— - This person is very hydrated.

Very hydrated.

And inside it, we’ve mixed our phages, so the most powerful ones in.. and it just pulls the artificial pee nice and slow through the tubing, And once we've done this, we take it to a nearby university where they actually— this is something brand new.

No one's ever done this before.

We're very excited— We CT scan them.

And you can see all the texture of the biofilm inside.

- Whoa!

- And I can show you some pictures if you’d like.

- So you CT the tube that you exposed to phage.

- Yep.

- Okay!

- And I can show you before and afters - Yeah!

- so you can see how well it works.

Oh, exciting!

And all this crystally stuff, - that's all biofilm.

- Whoa, so that's bacteria.

That’s bacteria, and they just hunker down in there.

So here is a nice clean cross-section.

And we have in blue, we have highlighted the bacteria on that crystalline structure.

And we can see that all except for that one little bit, - it's all gone.

- Wow.

- So the phages are really doing their job - They completely cleane.. and you can see it here, this is a sort of angled version, so you can really see how much of it there is.

And over here it’s just completely gone.

Wow, that's incredible!

So they were really, really, re..

It was really effective.

And so this isn't just for catheters and.. and preventing UTIs in catheterized people.

But this is also applicable to basically modeling what you could do in flushing out someone's actual ureter and bladder?

- Yeah, it's done a really great job.

- I love that.

The pictures are very promising.

Dr. Mel and her team have made huge strides in looking into phages.

And what's next is taking it into a clinical trial for human use.

And it seems pretty hopeful that phages can offer a really amazing alternative to antibiotic therapy for infections like UTIs.

But it's not just phages, which, to be fair, are one of my favorite solutions.

Teams all over the world are looking into all kinds of really cool science to help combat antimicrobial resistance.

Things like resensitizing bacteria to antibiotics, or taking inspiration from the original discovery and going out into nature and looking for fungi and other microbes that are producing antimicrobial compounds that we can take advantage of.

All it takes to come up with the solutions to some of humanity's most challenging problems is curiosity in the face of failure and many, many, many years of very difficult and dedicated work by lots of people, not just one guy.

Even though he was a fun guy.

I had to get it in somehow.

I'm sorry.

heartbreaking.

You know,