Flu Bang Goes the Theory

Year on year, millions of people all over the world are affected

by flu. Last year it killed nearly seven times more people than were

killed in road traffic accidents.

And every generation, a new strain emerges that can be catastrophic.

Flu is one of the most difficult diseases for modern

medicine to overcome, to predict or even to control. But why?

Bang Goes The Theory investigates.

I meet the volunteers infected with flu for medical research.

This whole ward is in quarantine lockdown

and the reason is on that trolley.

Jem gets to grips with why flu is so successful year after year.

This cascading explosion of viruses then burst back out of the cell membrane.

This is what's known as an influenza infection.

I'll meet the scientists trying to outmanoeuvre this

unwittingly smart virus.

The influenza virus is the great escape artist.

This is a high-security quarantine zone.

The people in here are receiving medical attention. But the

doctors are not trying to cure them. They're trying to infect them with the flu virus.

Because this is a clinical test to see how people deal with flu.

Ten volunteers are infected,

and their illness is monitored over three weeks to see how they fare.

It's only through research like this that we can learn

more about this virus.

How dangerous is flu?

In the UK we had about 12,500 deaths last year.

If you expand that to worldwide, there was something like half a million.

Then you have many more millions

where there's severe illness, where they're incapacitated

for a week or two or something,

your young, elderly and immune-compromised.

What's the difference between a cold and having flu?

Generally it is the symptoms you present with.

You can have your snotty, runny nose, a little bit of a headache, feeling unwell,

but if you start presenting more systemic symptoms,

you are feeling achy and have a temperature, that would probably be a good indicator.

But ultimately we need to have the laboratory diagnosis

to make that proper, formal diagnosis.

So what is the flu virus, and why is it so particularly deadly?

It's easy to think that flu is a modern disease.

The press is full of how new flus are crossing from birds and pigs

to humans in the markets of China.

But actually its history as a human disease goes back

a surprisingly long way,

to about 10,000 years ago.

Back then, big changes were

happening in the way we Homo sapiens lived.

We stopped being nomadic,

and started setting up permanent homes in communities, and that's

when many experts believe our flu problems began because we stopped

hunting and gathering and started farming and domesticating animals.

Until then, influenza was only an animal disease.

It infected birds, horses, wild boar...

And our contact with these animals was rare.

But when we started to raise animals domestically,

we brought them into direct, daily, physical contact

with other animals and ourselves.

And that's when a few viruses began to jump between species.

In these primitive farms,

many experts think that the virus first jumped from birds to pigs.

And then it was just a matter of time

until flu jumped again, to humans.

Human influenza can be a huge killer.

For instance, the 1918 outbreak of Spanish flu

killed over 50 million people.

But exactly how does the flu virus work?

For the purposes of what we're going to try, this is a flu virus.

Now, you may have heard flu viruses being given various names,

like H5N1, H7N9.

Well, they are important letters, those Hs and Ns,

because they refer to the proteins

that allow the virus to get in and out of cells within our body.

So on our virus, these fittings here,

these are like the Hs, the haemagglutinin.

And this one here, that's the N, the neuraminidase.

So there's the virus. Now, this is like the cell membrane.

It actually coats the entrance to my workshop.

This won't allow anything of this size through into the workshop,

the interior of the cell.

Once this virus drifts up towards the membrane,

if it has the correct proteins, the correct haemagglutinin,

it can...stick to the cell membrane.

And once it's stuck on there, the cell will invite it inside.

Once accepted, the cell membrane bulges in

and the virus comes in with it.

And then effectively seals back up again.

There you go. Once inside, this coating

starts dissolving away from the virus

and it's able to float towards the nucleus,

where it really starts doing the work.

And this is exactly what's happening inside the bodies of our volunteers.

The first of the flu viruses are passing into their cells.

Although at this point, they don't even know they're sick yet.

I'm feeling quite well at the minute.

I'm ready for it to come on all of a sudden, but I feel all right.

But inside their cells, the virus is starting to get to work.

The exterior of the virus kind of gets unravelled

as it travels through the fluid of the cell,

revealing what's inside.

Just eight genes.

The genes are the instructions as to how to build a flu virus.

Eight may seem like a lot, but it's not.

In fact, we humans have over 23,000.

And there's something else in the virus, too.

There's a chemical called polymerase.

We've represented this by a photocopier

because essentially, it does the same job.

It is the machinery required to copy these genes

so that more viruses can be made.

What it does now is pretty clever.

Because it hijacks the materials within the nucleus of the cell

and also its energy supply

to allow it to do its dastardly work.

Power going in.

Genetic material being loaded.

Gene instructions.

And so the process begins.

From when it enters the cell, within about five or six hours,

the virus is able to make thousands of copies

of its genetic instruction manual.

12 hours later, more and more of the volunteers' cells are hijacked.

Their immune system starts to react

and the patients finally start to feel sick.

Meanwhile, inside their cells, the virus is moving into a new phase.

Then these new, freshly-minted sets of genetic material

leave the nucleus and come out here, into the body of the cell,

the cytoplasm, where they start using the stuff around them

to assemble new viruses.

And within 24 hours, the virus could have reproduced itself

hundreds of thousands of times.

Two days into the experiment,

our volunteers are beginning to feel the full force of the infection.

Tiredness, nausea and a sore throat.

The virus is running amok.

This cascading explosion of viruses being created here

then burst back out of the cell membrane

ready to cause more mayhem inside your body.

This is what's known as an influenza infection.

A day later, and the volunteers

are showing the full range of classic flu symptoms,

from chesty coughs to sinus headaches.

My nose has been really, really painful,

and, like, they wake you up at 6:00 in the morning,

so when I was feeling really ill, I was just like, "Oh! Ow!"

When the virus enters the body,

there is an immediate immune response.

The subject experiences fever, that is a rise in the temperature.

That is one form of trying to kill the virus.

The subject will experience a runny nose.

And that runny nose is initially clear and watery.

As the cells that are acting to kill the virus die,

they are shed into the mucus.

The consistency of the mucus then changes,

to then being thick, greenish in colour.

And that's how the symptoms will progress.

But this patient's body is fighting back.

And swelling in the neck is a sign that it's working.

Because that's the location of the lymph nodes.

Now, these lymph nodes will actually process the virus,

the foreign body, soon realise that this is something that is harmful.

The cells start working overtime and the gland starts enlarging.

Because it now has to produce an immune response.

And that's why the glands then start feeling painful,

tender and enlarged.

These glands are swollen

because they are now pumping out cells to attack the flu.

Cells called antibodies.

Antibodies are special cells produced in the lymph glands

that can recognise and destroy specific enemy viruses.

So in the case of flu, for instance,

they recognise the neuraminidase and the haemagglutinin

on the surface of the virus.

Once recognised, the lymph glands go into overdrive,

producing billions of antibodies

which then destroys the virus.

But the flu virus can fight back.

And they can do this because of a weakness in the copying process

at the heart of the invaded cell.

Now, if this copying process was absolutely perfect

and made identical copies every time,

the human's defence systems would soon recognise that virus

and learn to kill it.

But crucially, the inadvertent genius of the virus

is that the copying process is not quite perfect.

And every now and again, it makes a set of instructions

that aren't quite the same as the original.

And those instructions then end up building a virus

that isn't quite the same as the original.

And that can result in a mutant virus.

And here you see there's been a subtle change.

A little bit of difference in the neuraminidase

and a little bit of difference in the haemagglutinin.

And these tiny differences are, in fact, what makes all the difference.

When the new mutant virus emerges

with its subtly-altered protein groups,

the body's police don't recognise it.

This process of evolving and changing to avoid detection

by the immune system is known as antigenic drift.

And the result is this virus can carry on and attack with impunity.

But we have one powerful weapon against this kind of flu.

We can vaccinate.

At any point in time, there are hundreds of different types of flu strain

circulating in the population.

And with modern travel, these are moving across the globe like never before.

Here at the National Institute for Medical Research in London,

teams of scientists work day and night

to find vaccines for the most dangerous strains

before they can reach our shores.

For us to decide what virus we want to use as a vaccine,

we have a global surveillance system

which is organised under the WHO, the World Health Organisation.

The first step in making vaccines

is collecting thousands of nasal swabs

from suspected influenza cases from all over the world.

We get specimens from virtually every country in Europe.

We go as far away as Hong Kong, South Africa, Argentina, anywhere.

Hundreds of these swabs arrive at the lab every day

and each has to be painstakingly analysed.

They are injected and incubated in egg yolks, where they multiply.

And after a few days, the viruses can be removed and tested.

What are we looking at here, then?

Where you see dots, that means we have no virus.

But where you see the red blood cells held in suspension,

that means we have virus growing.

-So we've got infectious virus here, here, here.

-Yes.

Thousands of flu strains are isolated like this,

but then the team have to work out the five or six strains

which are most likely to spread globally.

To do this, they study each virus' history.

This is the bible, is it?

This file contains the information we went through last September

to make vaccine decisions.

The file provides details about the flu viruses

collected from around the world and how they are evolving.

This shows an evolutionary tree.

And we're starting here with what used to be a virus, Perth 16,

which was a 2009 virus,

and up here, we're getting into 2013 viruses.

-So you can see how the virus has evolved.

-Oh, yeah, yeah, yeah.

And each of these little branches is an independent virus.

Within all this data lie the clues that can tell us

which new strains are likely to spread and cause havoc.

So you have to ensure you have the very latest viral strain

and then focus on that one to make a vaccine for the following year.

-Yes, but we draw on the world picture.

-Yeah.

Because if it was just happening in one small community,

one isolated country somewhere,

we would keep an eye on it, but wouldn't necessarily change the vaccine.

But if it was popping up in the US, in Europe, in Australia...

-Then it gets interesting.

-..bang!

-That's the vaccine for next year.

-Yeah.

But flu seems to always be one step ahead.

It takes a minimum of six months to produce,

test and distribute the vaccine.

And in that time, this new flu strain could mutate yet again.

The influenza virus is the great escape artist.

It is able to change its surface genes

to escape host immune responses

and so we are perpetually chasing it

rather than catching up and getting ahead of it.

-You won't be out of a job any time soon, will you?

-Certainly not.

Vaccines are a powerful weapon against flu,

but they are never going to beat it completely.

And crucially, many people just don't like getting vaccinated.

So oftentimes, the people who need them the most, like pregnant women,

aren't protected.

But a new vaccination policy could change all that.

Currently, we vaccinate the people most at risk

so they're less likely to get ill.

But perhaps this is the wrong way round.

Perhaps we should vaccinate the people

most likely to spread the virus in the first place.

Then the vulnerable wouldn't ever be exposed to it.

And new research is beginning to pinpoint

who is spreading flu fastest.

Five years ago, Dr Alma Adler started to investigate.

Since then, she has been recruiting children, teenagers and adults

to fill in an online flu questionnaire

to help pinpoint where the disease is actually coming from.

If everyone could just click where it says, "Log in."

Every year, the Flusurvey has been attracting thousands of users,

all giving the details of their lives

and when and how they are having flu.

What we're able to show is the rates of flu in the youngest age groups,

so in 0-18 year olds,

tended to peak before the older age group.

So you could see that you start to get increasing rates of flu

in the younger age group and then a week or so later,

the older age groups would start to go up.

The Flusurvey revealed where flu was actually coming from.

It was being spread by children.

When you had flu, who remembers maybe passing it to someone else?

Your mums or your dads said, "Oh, you've given me flu!"

OK, so, um... Right, there. Yes?

It was a nightmare for my family

because I passed it to my brother and sister

and then they somehow passed it to my mum and dad.

Who else have you passed it onto?

I also gave it to my other half of my family,

so the whole of my family was sick.

OK, so the whole family was ill.

School kids are constantly touching each other,

so if one has an infection,

it's likely to move between them. And fast.

But then the kids were passing the flu

on to their parents and grandparents

and into the high-risk groups.

And this suggested to Dr Adler a new way to control flu

was to stop it spreading at source.

To vaccinate kids.

If you vaccinate school-age children, they're going to get protected,

but there's more to it than that.

The theory behind it is that by vaccinating school-aged children,

you're getting the direct effects on those children

as well as the indirect effects to people they come into contact with,

so their parents and their carers, on an everyday basis.

They've come to the conclusion that

the best way of reducing the number of flu cases

is to vaccinate children between the ages of five and 16.

So this year, vaccination in children

is piloting in some schools in England and Scotland.

And unlike the adult vaccine, this is administered nasally.

It's hoped this revolutionary child vaccination

might make a serious impact on the spread of seasonal flu.

How did it feel?

I didn't really feel anything.

Is it something you'd be willing to have again next year?

I'll be looking forward to it.

But there is a different type of outbreak

that can cause far more serious problems.

And it seems to come around about once every generation.

It's called pandemic flu,

and we recently saw just how dangerous that can be.

The number of deaths in Britain

linked to swine flu has jumped to 29.

'It's reckoned there were 55,000

'new cases of swine flu last week across the UK.'

Between one and 3.5 people in the thousand who catch it might die.

That could mean anything from around 3,000 to 65,000 deaths

from swine flu.

For Charles Gardiner, catching swine flu was a life-changing experience.

In 2009, he caught what he thought was a common cold,

but it rapidly became much worse.

I don't know if it's a mother's feeling, gut feeling,

that things really weren't right with him.

Terrible coughing and sweats

and really gagging to get his breath. And I was really frightened.

That was like the start of the nightmare, really,

and we seemed to spiral from that moment

and we were rushed to intensive care.

All I remember is being at home and then just being so hot.

Like, just... I remember being on Facebook

and my status was, "I'm on fire, like, right now."

That was literally the last thing I remember.

His health quickly deteriorated

and over the next weeks, the flu showed no mercy.

He contracted double pneumonia, suffered heart stoppages

and multiple organ failure.

What could we do? I just obviously never left the hospital.

I was in the little room next to him.

And to see him like that, for such a big, healthy boy,

you know, just sort of...

I just couldn't believe it, how it all went.

But Charles fought back.

As a former England Under-21 international rugby player,

he was made of stern stuff.

You realise these were just stages of the swine flu

and you just hope you're going to come out the other end of it,

but you don't see it like that at the time, you just think,

"Oh, you know, this is... We're not going to get through it, are we?"

But we've got to, you know.

Really fighting for every minute, every step of the way for him.

Four years on and Charles has almost made a complete recovery.

Now you look back on it and you realise how lucky you are.

And now I don't have any long-term effects on my body or anything.

I am just so lucky to be like that now. Yeah.

When I heard his voice again, I thought, "Is that going to be different?"

They said, "He'll probably be very different,"

but he's not. He's just still Charles.

Thankfully for most people,

this pandemic wasn't as devastating as first predicted.

But pandemics are more serious than seasonal flu because

they are brand-new flu strains that emerge from animals.

Flu viruses can cause pandemics

when occasionally their surface antigens change almost completely.

Now, this results in a fundamentally-new virus strain,

which virtually no-one has been exposed to before

or raised antibodies against.

But how does this happen?

OK, so here's our flu virus again

with its eight genes inside it.

And we know how easily viruses from animals like pigs

can transmit over to humans,

but the thing is, animals can also be a very good source

of entirely-new strains of flu

that can potentially be much more dangerous to us

than the annual seasonal flu we're affected by.

And that's because animals can be infected

by two or more viruses at the same time.

Now, imagine this bale of hay is our cell

and you have two viruses infecting it.

Each different strain will have its own unique set of genes.

Now, during replication, some genes from one virus

can get mixed up with the genes from the other.

And this can produce a brand-new virus,

each containing some genes

from each of the original viruses.

And because it's a mix of genes from two separate strains,

the result is a novel virus.

And this is called antigenic shift. And it's what can lead to pandemics.

Because no-one has been exposed to this new strain,

or raised antibodies against it.

And this lack of immunity means occasionally,

these pandemic flu have the potential to be catastrophic.

In the spring of 1918, World War I was beginning to draw to an end.

Millions had already died.

And then a flu pandemic broke out.

It was called Spanish flu.

Some experts believe it started in a village in northern France,

others believe it started in the Far East,

but either way, its effects were overwhelming.

Spanish flu was a particularly infectious strain.

So aggressive, in fact, that many believe

it caused what's known as a cytokine storm,

a massive overreaction of the immune system.

And it wasn't just the very young,

the weak or the elderly who were affected.

Because the immune response goes into overdrive,

it was actually healthy young adults with a strong immune system

who succumbed the most.

Within 18 months, half the world's population had been infected

and at least 40 million people, some say up to 100 million, had died.

Since then, we've witnessed three other flu pandemics.

The less-severe outbreaks of Asian flu in '57

and Hong Kong flu in '68.

And, of course, the most recent, swine flu in 2009,

when another new strain leapt from pigs

to a five-year-old child in Mexico.

Within six weeks, this had also become a global pandemic.

It's estimated that up to 300,000 people may have died from swine flu,

but most suffered the symptoms and then fully recovered,

so this time, we were relatively lucky.

Outbreaks like these are completely unpredictable

and they spread in a matter of weeks,

so it's not possible to develop a vaccine.

Our current course of action is a group of drugs known as antivirals,

like Tamiflu or amantadine.

And these work by attacking the virus as it enters the cell.

But the virus evolves. It develops immunity

and these drugs then become less effective.

Currently, the best way to beat a flu epidemic

is something we all should be doing anyway.

Protect ourselves and others from getting the virus

by washing our hands scrupulously.

Now, you've got to do this properly,

so you start by really giving your hands a good rinse,

then you need to soap properly.

And by soaping properly, that means working between your fingers,

scrubbing away at your nails.

And the whole process should take between one and two minutes.

Do that frequently.

And that is it. It really is as simple as that.

And, if you are caught out without a tissue,

sneeze into the crook of your arm.

It might sound disgusting, but it's so much better than hosing the room

or catching the sneeze in your hand and spreading it everywhere.

Despite years of flu research, there's still much we don't know.

This year was a mild flu year,

but whether that was due to the warm winter,

the rain or a genetic quirk remains a mystery.

Either way, it'll be interesting to see

whether that new vaccination strategy made a difference.

But we still live under the threat of something more deadly.

A flu pandemic.

And only constant surveillance and scrupulous hygiene

can help us from that unlikely, but terrifying possibility.

Next week on Bang, the science behind flooded Britain

and what we can all do to make sure it never happens again.

If you want to find out more about careers in immunology,

check out the website at www.bbc.co.uk/bang.

And if you want to take part in the Open University's own flu survey,

follow the links to their interactive pages.