Defeating the Superbugs Horizon

All around us there is an invisible world.

The microscopic world of bacteria.

Some of these bacteria are going rogue,

becoming superbugs that we can't control.

They're probably smarter than I am.

They're able to adjust fire much quicker than me

so they're able to develop resistance a whole lot faster

than I can develop an antibiotic.

Antibiotics are one of the miracles of modern medicine

and scientists now worry that superbugs are emerging

which are becoming totally resistant to these drugs.

That's the scary day, that's the day when for some unlucky person

their day has come, right, that the drugs no longer work.

But researchers are engaged in a fight-back against the superbugs.

Bacteria have been on the earth for billion years,

humans have been on the earth a few hundred thousand years.

Right so, they have the accumulated smarts of eons of generations.

What we do have, as humans, is we have brains.

The rise of bacteria resistant to antibiotics

is being seen as a major public health threat.

So scientists are devising new and sophisticated ways

to try to defeat the superbugs.

Professor Hazel Barton is tracking down

one of humanity's greatest treasures.

To find it she has to venture

to one of the most untouched places on earth,

hundreds of metres underground.

It's finding a hole, nobody knows where it goes

and you kind of push and shove your way through,

and it's spectacular and it's beautiful

and you're the first person to see it and you leave the first footprints.

And so you get kind of a man in the moon feeling to be in there.

She's hunting for something that we all take for granted.

In these caves are tiny microbes crucial to our survival.

Where you want to go is where you can spot bedrock

and it's kind of dry but near enough the water that

that organic material can leach in.

And so somewhere like here, and you can see, this is one here.

These little dots of white here are the colonies of microbes.

So those are what we go in for and those are what we go after.

These tiny microbes are incredibly precious

because they can produce life-saving drugs we all rely on.

Antibiotics.

Professor Barton is going to the ends of the earth

because here she can find new antibiotics.

We need new ones, because the ones we have are starting to fail.

The last thing you want to do is go to the clinic, give someone

this drug that's gonna save their life, and it's not working.

Scientists like Professor Barton are going to such extreme lengths

because finding new antibiotics is fast becoming

the most critical concern.

Antibiotics are one of the miracles of modern medicine.

Since the discovery of penicillin in 1928,

they have revolutionized our lives.

They have stopped simple cuts

developing into life-threatening infections,

saved millions from diseases like cholera,

diphtheria and tuberculosis.

Antibiotics are so valuable because they stop and destroy

the bacteria that cause these life-threatening diseases.

But over the last decade scientists have witnessed outbreaks

around the world where antibiotics we have relied on in the past

have stopped working.

These outbreaks have been caused by new types of bacteria.

Bacteria that can sweep straight through our antibiotics,

and carry on growing.

These are the superbugs.

And we are becoming powerless against them.

But by studying these outbreaks,

scientists are hoping to defeat them.

The Brooke Army Medical Centre in Texas.

Just a few years ago, this renowned military hospital

unexpectedly found itself at the frontline

of the war against superbugs.

It started in 2006 when Master Sergeant Dan Robles

was just four months into his deployment to Iraq.

His unit was on a routine patrol, searching for a weapons cache.

It was about 2.00 in the afternoon, Baghdad time.

It looked like business as usual, cars driving back and forth,

people on the side of the streets.

It was quiet.

And there was just a big flash of light,

it sounded like I had my head in a bell

and someone was pounding on it real hard.

There was smoke everywhere.

The patrol had been hit by an IED

which tore into his side of the vehicle.

Sitting there in the Humvee after the explosion, I looked down

and I saw that one part of my leg, my calf muscle,

through the pants of my uniform.

And I didn't want to look down after that.

He sustained terrible injuries,

and ultimately the combat medics were unable to save his legs.

Within days, he was back on home soil at the Brooke Army Medical Centre,

but he was about to face an even tougher battle.

His wounds were infected and the usual antibiotics weren't working.

So they called in the Chief of the Infectious Disease Service,

Colonel Clint Murray.

You're not necessarily sure who the enemy is

when you walk in to see your patient.

I think it's very similar to what we do in combat,

is we try to figure out what we're doing who are we fighting?

Why are we fighting them?

Colonel Murray discovered that his patient had brought back from Iraq

three of the toughest superbugs to beat.

The first thing to do was protect the other patients

and control the outbreak.

So what we do is we try to isolate all our patients,

put them in their private rooms and before we go in

and out of those rooms, we put on gowns and gloves

to really prevent the bacteria from getting on us

so when we get to the next patient's room

we're not taking the bacteria with us.

Everyone does this,

so you'll actually see pictures of Presidents putting this stuff on

before they've gone into some soldier's room in the past.

It's just what you do.

Now he turned his attention to treating the infection,

but his usual arsenal of antibiotics just wouldn't work.

The number of antimicrobial agents we had were limited to treat them.

So in contrast to giving them the standard antibiotic

we give anyone that has a wound, we'd have to sort of

what we call is a bigger gun, but a more powerful antibiotic.

But these powerful antibiotics carry a risk.

They're not just toxic to bacteria, they can be toxic to people too.

I do remember Dr Murray explaining my situation to me,

and I was like, "OK, let's do it, whatever we've got to do."

Like most doctors, Colonel Murray has rarely used these antibiotics

because of the damaging side effects.

It had started to shut down my kidneys, I went into renal failure.

And so he comes back and says, "We've got to stop the antibiotics."

Based upon that, I really figured out, OK so here are the bacteria

and here's how we're helping you, but here's how we're hurting you.

I knew it was going to be a long fight

when it started doing more damage than good.

They had to keep changing the antibiotics

as each one became too toxic.

And this time it had shut down my immune system.

That was probably the most scary thing ever,

out of my whole ordeal.

No white blood cells, no immune system.

I had to wear a mask, I was in isolation.

Any cold, any...you know, the simple cold could have killed me

because I had nothing to fight it off.

Dan Robles is living a normal life back with his family,

but six years after the attack he still comes here

to check on his ongoing struggle with the superbugs.

Looking back over the two battles for his life,

his fight with the superbugs was the toughest.

When I was hurt, at least I knew that there was a chance

that I could survive, and that things were in place

to take care of me and fix me and make me better.

But as far as losing your immune system,

there was nothing that any doctor in the hospital could do

to keep me from getting the simple cold that could potentially kill me.

That was the scariest.

And it was scary because my family was right there with me.

And I was more worried about them watching something like that happen

than me coming back from Iraq in a box.

The Brooke Army Medical Centre experienced what happens

when a superbug enters a hospital.

Often the only choice for doctors is to use antibiotics

which themselves can be harmful.

The antibiotics that I could use ten years ago

are almost completely ineffective now

for some of the bacteria we have.

And often times we are resorting

to that last-ditch effort of antibiotics.

If we don't fix this issue,

we're eventually not going to have antibiotics.

The reason scientists are concerned is that over the last ten years,

antibiotic resistance has been growing across the world,

which has forced scientists to devise new strategies to combat it.

Dr Ruth McNerney is at the forefront of the battle against tuberculosis,

a disease caused by bacteria we thought we'd confined to history.

In the 18th-19th century,

tuberculosis was the biggest killer, full stop.

I mean, not just in infectious diseases.

In the middle of the 19th century, life expectancy was just 41.

In this time before antibiotics,

diseases like TB spread through the crowded and cramped streets.

It transmits very easily through the air

so it's very hard to avoid getting TB,

you don't know you've been exposed,

you don't have to do anything to catch TB, except continue breathing.

It would just affect everyone. Young and old.

One of the great achievements of modern medicine

was the defeat of this disease with a cocktail of antibiotics.

Today, over 8 million people live in London

without giving a thought to TB.

But our crowded cities are still the perfect playground for bacteria.

We pour into the city every day, we pour down the tube,

on to buses, out round the streets.

If someone had infectious TB,

and they were coughing out the tiny droplets

then it would be very easy to infect so many people.

It would spread very, very easily.

Now if we can imagine that we didn't have the antibiotics to treat TB,

well, we'd be in big trouble because that's the only way

we can stop TB spreading.

But the fear now is that our achievement

in controlling this disease is being threatened.

Dr McNerney is seeing a rise in cases of antibiotic-resistant TB.

We're now seeing the emergence of strains of TB

that are resistant to the drugs.

And that's becoming quite a serious problem.

One of the issues is that we don't know how much drug resistance

there is because it's actually quite difficult to measure.

For now, the resistant strains showing up in the UK

can still be treated by a small number of antibiotics.

But outside the UK, Dr McNerney has seen a new strain of TB emerge

that is resistant to all of the antibiotics we have to treat it.

It could arrive tomorrow on an aeroplane. It might already be here.

We don't know. We just have to be on our guard.

We just can't afford to let this genie out of the bag.

Scientists are now trying to understand

exactly how superbugs have gained resistance,

and, ultimately, how we can defeat them.

Here at Harvard University,

scientists are investigating why some of our antibiotics are failing.

It's an experiment that happens in Professor Roy Kishony's lab.

Here they are deliberately trying to create superbugs.

This is a new device we've developed - we call it the morbidostat.

Using the morbidostat, they are going to produce a highly resistant version

of a harmless strain of a bacteria we all have in our gut.

E. coli.

At the beginning you have bacteria just growing

happily in the tubes, they have enough food, they are growing fast.

They start by trying to kill the E. coli

by dripping in a low concentration of antibiotic.

But as the millions of bacteria have been multiplying in the tubes,

some, by chance, will have developed mutations

that allow them to be resistant to the antibiotic.

This mutant would start replicating faster than everyone else,

ultimately it would take over on the whole population.

So now they try to kill this new mutant strain.

They up the strength of the antibiotic.

Again, most of them die.

But a new mutation appears,

that can survive the even stronger antibiotic.

And then we see another step, now they can grow

in even higher drug concentrations,

so we keep iterating this process over and over and over.

This experiment shows that bacteria become resistant

by being exposed to low levels of the very thing we use to protect us,

antibiotics.

Now the team have created a new experiment to find out exactly

what is happening in these mutant bacteria to allow them be resistant.

It starts with what is in effect a giant Petri dish.

We're setting an experiment really for the first time

in which we're going to let bacteria swim against

an ever-increasing concentration of an antibiotic, and see what happens.

The jelly contains food for the bacteria to grow,

but each slab is infused with an increasing concentration

of antibiotic, which should act as a barrier, killing the bacteria.

First slab is no drug,

then about the amount needed to kill the bacteria,

then ten times more, 100 times more, and 1,000 times more.

The experiment begins with a tiny drop of E. coli.

They're certainly going to spread when there is no drug but

we want to see can they actually go to the place where there is an antibiotic?

A time-lapse camera captures the spread of the bacteria.

As the experiment begins, it's easy for the bacteria to grow

in the first section, with no antibiotic.

Where there is no drug, it's very easy for them,

there's food but no stress.

Then they hit the boundary where the drug concentration increases.

At the barrier where the antibiotic starts

at the first concentration, the spread is halted.

They get stuck there for a while,

they try to go into this area because there is food,

but every time they try to go into it they get killed by the drug.

But that doesn't last long.

Very soon, a mutant appears that can break through the barrier.

Whole new colonies grow that can live happily

in this concentration of antibiotic.

And it doesn't stop there, this happens again and again,

even up to 1,000 times concentration.

At the end of the experiment we are the maximal level of solubility

of the drug, we just cannot add more drug, it doesn't dissolve anymore.

This carefully controlled epidemic

all happens in the space of just one week.

The team is beginning to pick apart these mutant bacteria

to see exactly how this is happening in the presence of antibiotics,

by peering inside the bacteria, at their genes.

What actually happen under the hood,

when we open and look at the genomes of this bacteria.

We can do it now, we can sequence a whole genome of these bacteria

and see what are the exact changes that happen.

Typically, what genes changed and allowed them to mutate in such a way

it can grow in this higher drug concentration.

This is evolution in action.

Over millions of divisions, the bacteria's DNA changes.

Evolution happens here fairly fast,

in basically two weeks of experiment

we see a very dramatic increase in drug resistance,

1,000-fold increase in drug resistance.

So, yes, you might want to say evolution is happening

in front of our eyes, as we speak.

Used properly, antibiotics can kill bacteria and save lives,

but as these experiments show,

low levels of antibiotics encourage bacteria to develop resistance.

In the real world too,

our use of antibiotics may actually be causing more superbugs to emerge.

Superbugs were once rare and infrequent,

but they are now showing up across the world's major cities.

Professor Tim Walsh studies these newly emerging outbreaks,

and there's one region that concerns him most of all.

The southern Asian continent suffers from antibiotic resistance

far more than probably any other area on the planet.

For the last three years he's been travelling to Southern Asia

to understand why some of the poorest parts of the planet

are superbug hotspots.

He's on his way to Karachi's Civil Hospital, in Pakistan.

In both rich and poor countries,

resistant bacteria cause their most costly and deadly infections

in the places where people are most vulnerable - hospitals.

The doctors at the hospital are working with Prof Walsh

to identify and improve the conditions contributing to the spread of superbugs.

A lot of times you see them and they're not washing their hands.

This is one of the reasons we have so much infection.

I think the infection control issue here

clearly seems to be very important.

One of the key issues in places like the Civil Hospital

is sort of overcrowding of the wards and lack of infection control.

Windows are open so bacteria can kind of blow into

intensive care units etc, and there seems to be a lack of

understanding as to the importance of things like hand-washing

in moving from patient to patient, or indeed from ward to ward.

The doctors are facing dangerous infections,

in impossible conditions.

Professor Walsh has found

there are no dedicated infection control teams,

insufficient bacterial diagnosis, and no isolation rooms.

Well, the people in Karachi know about their limitations,

and that's the great thing, they're very open and honest about them,

they realise they must do something about it.

But there's another factor at play that the hospital can't control.

There is an easy availability

of the very thing needed to create superbugs.

In most parts of Asia, antibiotics can be purchased

freely from shops without prescription.

A problem that the doctors throughout the hospital

are aware of.

From the pharmacy right outside the hospital

I bought all these antibiotics and they cost me just 2.50 rupees.

Anyone can go and buy these.

Bought over the counter, antibiotics are misused and misunderstood,

taken even for things that they can't cure.

And there are no instructions, certainly not with these, on usage.

Yeah, they don't come with a leaflet.

And a lot of people just will go to the corner shop

and simply buy a whole range of antibiotics and simply self medicate

and you can see on this one here one tablet has obviously been sold

to one particular person - just to take one tablet is just crazy.

You're just exposing the bacteria to what we call

sub-killing-concentrations of that antibiotic.

And so you're actually not killing the bacteria, or indeed

preventing it from growing, and more or less all we're doing

to the bacteria is saying,

"OK, here's the antibiotic, become resistant."

It's not just the sale of antibiotics that's unregulated.

Elsewhere in Asia, outlets from the industrial-scale manufacture

of antibiotics have contaminated rivers and streams.

As a result, societies can be awash with antibiotics,

the perfect conditions for superbugs.

However, the conditions needed to create a superbug

are not just happening in Asia, but right across the world.

Professor Lance Price is a superbug tracker.

A few years ago, he was called to investigate a superbug

which helped to reveal how another use of antibiotics

was driving resistance.

Bacteria are everywhere. They're a natural part of our environment,

they're a natural part of us, in fact human beings are sort of

a walking ecosystem, we have bacteria that live in and on us,

one of the bacteria that I'm particularly interested in

is Staph aureus.

It's estimated the between 20% and 30% of humans

are colonised with Staph aureus,

and most of the time it doesn't pose a problem.

If Staph aureus does cause an infection, it is usually

straightforward to treat with an antibiotic called methicillin.

But when it develops resistance to methicillin

it becomes a superbug we've all heard of, MRSA.

This is a picture of methicillin-resistant Staph aureus.

Methicillin-resistant Staph aureus and regular Staph aureus

don't look any different in a photo like this,

but when you look at the DNA, you'll see very distinct differences.

MRSA carries genes that make it resistant to methicillin,

that's why we call it methicillin-resistant Staph aureus, or MRSA.

He uses these genetic differences as clues

to lead him to the source of the outbreaks.

We crack these cells open and we sequence the DNA,

and then we use that to trace the evolutionary history of these bugs

and determine how and sometimes when

they became resistant to methicillin.

Three years ago, he discovered a new strain of MRSA

in 18 different countries, including the USA and in Europe.

And there was one thing that seemed to connect them all.

A new strain of MRSA emerged that we'd never seen before,

and when we started tracking it back we found out that

most of the people who were getting it were actually employed in the

livestock industry, so people that had direct exposure to food animals.

And that set off an investigation for us.

The genetic trail revealed this strain of MRSA

had passed into these people from pigs.

But then they went further.

They tried to follow the genes back to a time before

the MRSA became resistant.

And what we found was a big surprise to us,

we found that in fact that this new strain had started off in people

but it was not MRSA, it was just Staph aureus, or SA,

it spread to pigs, and that's where it became resistant to methicillin.

Professor Price had discovered that this ordinary Staph aureus bacteria

had mutated while it was in the livestock,

to become potentially deadly.

To him, the reason was obvious, antibiotics.

The simplest explanation is that we're using

lots and lots of antibiotics in food animal production.

Most of the time they're just being added to animal feed,

so they're being mixed in giant silos of feed

and given on a routine basis, just basically with every meal

that animals are getting a little bit of antibiotics.

Many farmers thought it was the best way

to keep closely packed animals healthy

and for them to grow faster,

but Professor Price believes the superbug he was tracking

was created as a result of this kind of antibiotic use.

We're raising animals under the conditions that we know

lead to the spread of bacteria between people,

and then we add the magic ingredient which is antibiotics,

which just virtually guarantees that we're going to have

drug-resistant bacteria.

In 2006, the European Union banned the use of antibiotics

as growth promoters in animal feed.

But elsewhere in the world, it is still being used in vast quantities.

In the United States we use 29 million pounds of antibiotics

every year in food animal production.

I mean, you know, these are the crown jewels of modern medicine,

they're being used like cheap production tools.

There is a movement in the US to change this practice.

Professor Price is working with farmers who are trying new ways

of keeping animals healthy,

without constant use of antibiotics in the feed.

-Like to come in and see what we're doing here?

-I would.

Yeah. Give you some coveralls and some booties for you.

Removing antibiotics from the feed means farmers need to take

other measures to avoid their livestock getting infections.

I have to wear these in a lab sometimes.

In that case, we're protecting ourselves from the microbes

rather than the turkeys from us.

But working this way means farms are less likely

to encourage superbugs to emerge.

Everybody would say,

"There's no way you're going to be able to grow turkeys without antibiotics."

So we started trials and learned from that,

that we needed to give the birds more space

and really go out of your way to have the best animal husbandry,

that they don't get stressed.

And now, if we do get a sick flock, which is rare,

but if we get one and we have to treat it,

we can use the simplest antibiotic like a tetracycline,

and it usually works great.

For where it continues, large-scale use of antibiotics in animal feed

can create the right environment for superbug emergence.

Bacteria don't wear lapel pins.

They're not confined to any geographic area,

and so what we do here in the United States can potentially impact you.

So as we create these multi-drug-resistant pathogens,

those pathogens can then spread around the world.

And so you should just be as concerned as I am

about what we're doing over here.

Wherever a superbug outbreak occurs in the world,

doctors across the globe start to worry,

because regardless of where they first emerge,

a superbug can soon become a citizen of the world.

We carry about 100 trillion bacteria in us,

therefore, when we travel the world, they travel the world.

Any types of resistance that occurs in one country

can very easily be transported around the world, almost in real time.

With the rising levels of air travel,

resistant bacteria have hitched rides across the globe.

Probably in about the last 15 to 20 years,

we've managed to contaminate the whole of the planet.

If you go to the north of Norway, or even down into Australia,

down to Tasmania, you will find these type of resistances.

Not only are superbugs being found all over the world,

scientists are finding that these bacteria

are becoming harder and harder to treat.

It's this problem that Professor Tim Walsh grapples with every day.

This a very quick illustration of how resistance has evolved

over about the last 20 years.

Each white disc on these plates contains a different antibiotic.

A clear circle indicates the antibiotic is working

and killing the bacteria.

This E. coli from India about 20 years ago

is fully sensitive to the series of antibiotics

which we would use to treat E. coli infections.

12 years ago, the E. coli had started to become resistant

to some of the antibiotics,

but the newest strain has shown unprecedented levels of resistance.

You can see here it's virtually totally resistant.

The only antibiotic that shows any activity

against this particular organism, is this antibiotic here,

which has some issues with toxicity,

and it's at the moment about 40, 50 years old.

We're starting to have a bit of a renaissance with it,

because clearly you can see that we have nothing left.

We are beginning to see this level of resistance appear

all over the world.

Bacteria that only respond to a few rarely used antibiotics.

And the trouble is,

these antibiotics of last resort can often be toxic themselves.

Scientists believe there is an urgent need

to re-stock our arsenal with new antibiotics.

It's a hunt that has taken Professor Hazel Barton across the globe.

I get to travel the world, I get to see amazing things,

so I just love it!

You might think that new antibiotics were created in a lab,

or discovered deep in the rainforest,

but actually most of them have been found in the dirt.

Almost all of the antibiotics that we use now

have come from soil micro-organisms.

The procedures that we have in the lab for finding antibiotics

is literally to pull the microbes out of this dirt and grow them.

More than three-quarters of the antibiotics we regularly use

in hospitals today were taken from microbes in the soil.

And the trouble is, we've been doing that for 50 years

and we keep finding the same things.

And the best microbes for producing antibiotics are bacteria themselves.

To find new antibiotics, Professor Barton has to hunt down new bacteria

in some of the most untouched places on Earth.

Hundreds of metres underground.

Oh, it's slippery here.

For bacteria,

these caves are one of the toughest places in the world to survive.

Between where we're standing right now and the surface,

there's about 1,000 feet of rock.

So for anything that's happening on the surface,

all that energy from plants and animals, for that to come here,

it has to get through all that rock, and it can't do that very easily.

So we end up with a very starved environment,

where there's hardly any energy available.

These caves may look peaceful and still,

but they are, in fact, a battlefield.

With so few resources available,

bacteria must fight each other to survive.

They become either much more careful of their resources

in defending them,

or they get a lot more aggressive in stealing someone else's resources.

They do this by producing an arsenal of chemical weapons.

Professor Barton has been collecting these weapons

in the hope they might be used as antibiotics.

Last year, she captured one type of bacteria

that produced over 38 different bacteria-killing chemicals.

To put that in perspective,

there's only about 40 antimicrobial drugs in the clinic right now.

So one bug from this cave was able to make

almost as many as we have available to us in the clinic.

Not all of those are going to be useful as medicines,

but the potential becomes huge.

I mean, we've pulled out 4,000 microbes,

so it's almost like a chemical universe

and we are kind of playing on the edges of it

with antimicrobial compounds and there's this huge vast

unknown space that we've yet to kind of explore to see what's out there.

The work of scientists like Professor Barton

is becoming increasingly important, as any new antibiotic discovery

will enable us to retain our hold over the superbugs.

But eventually, bacteria will always find a way to become resistant

to even the new antibiotics.

If we are going to finally overcome the problem of resistance

we are going to need a whole new approach.

On the face of it, this seems an unlikely place to discover

a new strategy for fighting superbugs.

It's a sewage works in Buckinghamshire.

But microbiologist Dr David Harper believes the answer

may be found here.

He's hoping to exploit the weapons technology of a creature

that has developed its own way to fight bacteria.

Bacteria have been on the Earth for billions of years.

That's why they're so tricky.

But there's something else that's been on the Earth

for billions of years.

And it knows how to deal with bacteria.

That's what I'm here to collect.

-Good to see you.

-And you, David.

-Let's go and get some good ones.

Raw sewage is the perfect breeding ground for bacteria.

But that also makes it the ideal home

for the ultimate bacterial predator.

He wants to enlist that predator to fight for us in the superbug war.

In there, although we can't see it, there's a war going on.

There are billions of bacteria struggling for existence,

and tens of billions of bacteriophages.

Viruses that only and specifically affect and kill bacteria.

And they are fighting in there, as we speak.

Just like humans, bacteria can be infected and killed by viruses.

Bacteriophages are the most common and diverse predators on Earth.

There are 10,000 billion, billion, billion,

bacteriophages on the planet.

We haven't actually counted, that is an estimate.

Dr Harper wants to get these bacterial viruses

fighting on our side in the superbug war.

"Bacteriophage" literally means "bacteria eater".

They work by landing on the bacteria,

injecting in their own DNA,

then reproducing themselves inside the bacteria until it bursts.

Back in his company's lab,

Dr Harper is attempting to harness the power

of these bacterial predators.

It's a tricky business.

To kill disease-causing bacteria,

you need the particular phage which attacks that bacteria species.

We go and collect the sewage, we bring it back here,

we put the sewage into a culture of the target bacterial species.

There are lots of different phages in there,

I said there were billions - there are. Maybe thousands,

maybe hundreds, will hit that particular species.

In a few cases, you might have a species where only a few will hit it,

but still, if they're there, they will bind,

they will kill, they will multiply

and you can pick them and grow them.

Using viruses to kill bacteria

sounds like an attractive idea in principle,

but in practice, working with live organisms has proven difficult.

But Dr Harper is drawn to this field of research

because phages offer one significant advantage over antibiotics.

Antibiotics can't change.

If the bacteria generate resistance, that's it,

you need a new antibiotic.

With phages, the bacteria are their lunch.

If they can't multiply, they die out. If they can, they grow.

So when the bacteria change, a few phages will be in there,

which can grow in the new ones.

That mutation is then preferred, those phages will multiply

and come to dominate.

The bacteria will change again, a few of those will be able to grow,

they grow again, they amplify, they come to dominate.

It's an arms race.

Tapping into this arms race would hand us a key advantage

because the bacteriophages are able to evolve.

If we are able to enlist them to fight for us,

they will keep fighting for us, even as the bacteria change.

They are in many ways a perfect drug, in many ways they aren't.

One of the most telling things against bacteriophages as drugs

is that nobody has yet developed one.

Dr Harper's company have seen some early successes

and are now planning a trial to treat lung infections

often affecting cystic fibrosis sufferers.

We hope that the results in cystic fibrosis will be convincing.

We hope to move on to the large clinical trials

of hundreds of patients, which will underpin

progressing this to market to improve people's lives, to save people's lives.

There's a long way still to go, but we're working on it.

Right now, phage medicines are still in the very early stages

but new developments in understanding exactly how

bacteria become deadly are giving hope that there could be

another way to outsmart them.

Princeton University in New Jersey.

Here, a team are taking a radically new approach,

one that has led to an unexpected breakthrough

in the fight against deadly bacteria.

Professor Bonnie Bassler has spent her career

getting in to their world.

I love bacteria. I think most of the things

they do on this earth are fantastic and essential,

but bacteria have features, bells and whistles, different processes,

that they are, that they have for fighting in their own environments.

And when those get unleashed in a human or in an animal

or in a plant, it can kill us.

With antibiotics, we have been attacking bacteria,

forcing them to evolve resistance.

But Professor Bassler thinks that we may not have to be so aggressive.

Instead of just smashing them to smithereens

like we've done with traditional antibiotics, if we could learn enough

of their secrets, and get them to spill their guts a little bit

and tell us how they work, we could just get them to behave.

And do behaviour modification instead of killing them.

Compared to us, bacteria are so incredibly small

that on their own, they shouldn't be able to hurt us at all.

If one or a few bacteria release

their mostly deadly arsenal of toxins, they have no effect.

I mean, this is not a David and Goliath, this is like

way beyond that, so the question is,

how can these bacteria have us on our knees,

right, how can it be that they can actually kill us?

Bacteria don't attempt to attack us on their own,

they wait until there are enough of them and then act all at once.

You can think of the bacteria, each individual bacterium as a soldier,

and so you have these masses of soldiers, but it's only useful

when somebody says "charge", right, so the question is

what's the information that tells the bacteria now is the time to attack?

If we could find a way to stop the bacteria attacking together,

they wouldn't be able to harm us.

But understanding how they co-ordinate their attack

is incredibly difficult

because bacteria are hidden from sight.

But there is a type of bacteria that you can see,

and they have a rather unusual relationship.

The Hawaiian bob-tailed squid is a master of disguise.

In the day, it disappears into the sea bed,

but when it comes out to feed at night, it's even more ingenious.

At night, this is like the stealth bomber of the ocean,

it likes to cloak itself in an invisible device.

If it were to just swim around,

the starlight or moonlight would hit its back

and it would cast a shadow on the sea floor here

and then predators that could see that shadow

could calculate its trajectory, and eat it.

To eliminate their shadow,

these squid project light down onto the sea floor.

So by matching how much starlight or moonlight hits its back

with how much light comes out of its body, there's no shadow.

So it's a fantastic sleight of hand, sleight of tentacle,

if you will, it's a fantastic anti-predation device

because it makes it invisible at night.

And this incredible invisibility cloak is created by bacteria.

There's a bacterium that lives in the body of the squid,

the bacterium's name is Vibrio ficheri, and it makes light,

so the squid gives the bacterium a home,

the bacterium gives the squid light,

and the squid uses the light to protect itself from predators.

But just as a single dangerous bacteria would not be enough

to make us sick, a single glowing bacteria would never produce

enough light to help the squid.

For the bacteria to be useful, there must be lots of them.

So the bacteria wait until there are enough of them,

and only then, all start glowing at exactly the same time.

When this was initially discovered,

the idea that bacteria could do something as a group was revelatory.

The bacteria were working together,

but the question was, how were they doing it?

The beauty of these marine bacteria is that they glow in the dark,

so they could experiment to see what exactly caused them

to start making light.

They discovered the bacteria were producing a chemical messenger -

they were talking to each other.

As they grow and divide,

they all make and release these molecules.

When there's more cells, the molecule outside the cells

increases in proportion to cell number.

And when the molecule hits a certain amount,

the bacteria have receptors on their surfaces, they detect that the

molecule is there and then they all change their behaviour in unison.

Using these molecules, the bacteria were able to detect

when other bacteria were around them.

And by communicating with each other, the bacteria were able to

achieve something they could never achieve as individuals.

This behaviour is called quorum sensing.

Sometimes, the way I think of it, is if you want to move a piano

from over there, to over there, you don't try to do that yourself,

you get all your friends, everybody grabs and you say,

"One, two, three, lift."

And then you can carry out this task as a co-ordinated synchronous group

that you couldn't do, if you were just acting on your own.

Once they'd discovered the glowing bacteria could talk to each other

using chemicals, Professor Bassler began to wonder if this was the way

dangerous bacteria were coordinating their attack.

And so I thought, "Well, I wonder if anybody else makes this molecule."

So I just collected every bacterium I could get my hands on.

And every bacterium I tried that with, it worked.

And there was this moment, I still get goose pimples with that,

there's this moment where I thought,

"Holy cow, they're talking between species,

"they all make this molecule."

It looked like all bacteria could communicate using these molecules.

This had incredible implications.

If she could interrupt these conversations,

she could get the bacteria to stop their group behaviour.

We know what these molecules are, at least some of them,

these quorum-sensing molecules, so we've made antagonists, right,

molecules that look kind of like the real things,

but they jam the receptors.

And so if you add those, it's like static, you know,

you add these anti-quorum-sensing molecules, the bacteria can't hear.

Professor Bassler had found a way

to stop the glow-in-the-dark bacteria from talking.

Could she do the same with dangerous bacteria

and prevent them from launching their attacks?

We started this work with Vibrio haveri and Vibrio ficheri,

these beautiful bio-luminescent bacteria,

but they have a nasty cousin, Vibrio cholera.

Those two bacteria make this beautiful light, this guy kills you.

Although completely eradicated in the UK,

the cholera bacteria is responsible for over 100,000 deaths

in the developing world every year.

So we transferred what we learned

from the glow-in-the-dark bacterium to this bacterium.

Professor Bassler can measure the level of a protein

that cholera bacteria produce that makes them deadly.

This is the protein that cholera makes

that lets it adhere to your intestine.

It has to make this. It's step one in the infection

and that makes it virulent.

So then what we did was, we added our anti-quorum-sensing molecule

at different amounts to cholera cells,

and if we add more and more and more of our molecule,

what you can see is,

it makes cholera incapable of making that virulence protein,

and incapable of making an infection.

This is just the beginning for Professor Bassler and her team,

as other researchers around the world are now investigating

whether this method of silencing the bacteria

has the potential to work where antibiotics are failing.

Scientists have entered a new stage in the battle with superbugs.

It may be that we have underestimated our enemy.

They're probably smarter than I am.

They're able to adjust fire much quicker than I can

so they're able to develop resistance a whole lot faster

than I can develop an antibiotic.

But around the world, scientists are taking up

this cat and mouse challenge.

It is a game. They're playing their game and we need to play our game.

We each need to do our best move.

We are understanding bacteria better than ever before

but maybe we don't have to triumph over all,

we just have to stay one step ahead.

We don't have to totally win, that's not the goal.

The goal is simply to find out enough to be able to do something useful

and then let the next scientist find out the next thing that's enough

to do something useful.

Subtitles by Red Bee Media Ltd