Good evening.
I am Professor Jonathan Van-Tam,
Deputy Chief Medical Officer for England.
And many of you may have seen me
giving public health announcements from the podium
at Number 10 Downing Street.
But tonight is different.
Tonight, I am speaking to you as a scientist and a doctor,
not a government adviser.
Welcome to the Royal Institution Christmas Lectures.
Tonight, we're going viral!
APPLAUSE
Wherever there's life on this Earth, there are also viruses.
And there are actually more viruses on the Earth
than there are stars up in our universe.
And to be perfectly truthful, most of them are harmless to us.
And some of them play vital, hidden roles, for example,
recycling nutrients back into the oceans.
But some are deadly
and just one infection
can lead to a global pandemic.
The first respiratory virus pandemic
of the 20th century was in 1918,
and it was the H1N1 influenza virus.
And we think that that killed 50 million
people around the world, and that's more than actually were killed
by World War I, which had taken place over the four preceding years.
And at the time, there were no vaccines.
All we had was isolation,
quarantine,
face coverings.
And keeping social distance.
Does that sound familiar?
FAINT CHUCKLING
Well, since then, we've had many crises.
We had the HIV pandemic in the 1980s.
We've had crises due to Ebola and also to Zika,
and now we find ourselves here in the middle of a pandemic
caused by the SARS-CoV-2 virus, SARS coronavirus.
The disease that comes from it is called Covid-19,
and right now, we're still battling the latest twist in that story,
in terms of the Omicron variant.
That's the kind of bad news but the good news is, in the past
two years, we have had absolutely amazing scientific learning
and achievements on an unprecedented scale.
For those of you who are going to be scientists,
being a scientist is a team game.
You can't know it all and do it all on your own.
And for that reason, over these three lectures that are coming
up now, I am going to be joined by some top
scientists from around the world who have each played a vital
role in this pandemic and getting it under control.
Now, to explain the secrets of viruses
and how our immune system fights them,
our first expert tonight is somebody who helped develop
the AstraZeneca vaccine at Oxford University.
Will you please welcome Professor Katie Ewer!
So I'm an immunologist, which means I study how our bodies respond
when viruses attack us, and I also develop vaccines that help to
train our immune system to learn to fight back.
Now as we've seen over the last two years, rapid development
of vaccines against Covid-19 around the world, that success has been
built on decades of research to understand infection and immunology.
But before we can all understand a bit more of that tonight,
there's a few things that we all need to know first.
What are viruses? How do they work?
And how does our immune system fight them off?
Well, to start with, let's see just how small viruses are.
And what we've got here is a model of a human hair that we're going
to enlarge about 4,000 times, so after three...
ALL: Three, two, one!
WHIRRING
So in real life, this human hair would be about 80 micrometres across
but when we've blown it up 4,000 times,
it's now about 30cm across, and at this scale,
we can start to see lots of things on our body in a lot more detail.
So for example, here, we've got
some little models of human skin cells and these have been
blown up 4,000 times as well, just like our hair.
So if we look here, you can see now, on this scale,
a human skin cell is nearly the same size as my hand.
And we've got some other bits over here as well.
So if we were to blow up an E coli bacteria,
this is a bacteria that can causes infection in all of us,
in real life, E coli would be about two micrometres across
but blown up at this scale...
..it's like this, it's about this size.
But viruses are even smaller than bacteria.
And if we were to blow up a SARS-CoV-2 virus,
the same amount as we've blown up this hair,
they would be about the same size as these poppy seeds.
So still really difficult to see.
So in order to see viruses in a bit more detail, we are
going to have to zoom in even further. Now to do this,
we've had some help from the pupils at Biddenham International School,
and they've been incredibly busy crafting these beautiful
models for us of different types of viruses,
so that we can see their shapes in more detail.
In fact, we've almost got like a whole virus zoo here.
So viruses can have these quite simple geometric shapes
but as we know, their primary purpose is to replicate,
and when they do that, it can be really bad for human health.
So, JVT, do you want to tell us
a bit more about some of these viruses?
Yeah. I recognise some of these
and this one is the one I've spent most of my life studying.
It's the influenza virus, and this is the one that gave us
a pandemic in 2009, the swine flu pandemic.
It's also the one that gave us the 1918 pandemic
that I talked about at the beginning, and this one
will give you a sore throat, a cough, a runny nose, and a fever.
Now, this one over here, I'm afraid, Katie,
if you get this one, you're going to get diarrhoea and vomiting.
This one is the norovirus.
And this one up here, this is a real nasty.
This is the rabies virus,
and this one attacks the nervous system,
and it also, I'm afraid, can attack the brain.
It's really very serious, that one.
So as we've seen here, we've got lots of different viruses, they can
create lots of different symptoms in different parts of our bodies.
But all of these viruses are built of the same stuff.
On their outside, they have a protein coat.
But, what's on the inside of a virus?
So, we're going to look at that in a bit more detail
and in order to do that, I would like a volunteer from the audience.
Erm,
here in the red top with the monkey on. Yeah.
Would you like to come down?
So, what's your name? Emily. Hello, Emily.
What we've got here is a coronavirus.
And we want to know what's inside it.
Can you think of a way that we might be able to open this virus up?
Fuse here. Something to light it with.
Yeah, shall be have a go at lighting it?
Would you like to put these on for me? OK.
And this is just a clicky lighter, like that.
So you hold that and what I'd like you to do is hold it
right at the end here, and then, we're going to have a countdown, OK.
So we're going to light the fuse. Go on, press it really hard!
That's it. Great. Now, come stand over here with me.
ALL: Three, two, one.
CLICKING
LAUGHTER
Thank you very much. You did a great job there, Emily.
Do you want to give me your glasses back?
Thank you. You go and sit down.
So inside the virus is its genetic material,
either DNA or more commonly for viruses, RNA.
And on here is the recipe that viruses need to replicate.
And it's shown here as the genetic code, which for viruses, for RNA,
is written as A, G, C and U.
And as you can see,
there are lots and lots of letters written on this piece of paper.
It's quite a long roll so, JVT, can I have a hand to unroll this?
And we'll just see quite how big this recipe is.
You can see it's really long.
There we are. Right at the end.
So, Katie, how many letters are on the code for this virus?
Does anyone in the audience want to have a guess?
Do you want to shout out how many letters they think are on here?
1,000 million?
AUDIENCE OFFERS SUGGESTIONS
Well actually, some of you were pretty close.
It's about 30,000 letters.
Now, that might sound like a lot but if we were to turn that into digital
information and store it as a file, it would be less than one megabyte.
So these are the simple instructions that the virus needs
to be able to replicate.
But the thing about viruses, they can't do this by themselves.
They need a host to be able to reproduce and survive.
So Katie, if viruses
needs another organism to multiply
and survive, are they alive?
Or are they dead?
Let's just see what the audience think.
First of all, if you think a virus is alive,
put your hand up.
OK.
That's about 30% or so, I'm guessing.
And if you think a virus is dead,
put your hand up.
Oh, that might be slightly more.
And if you're really not sure, and you can't decide,
put your hand up now.
Just a few. Katie, what's the answer?
Well, JVT, I'm going to let you in on a little secret
which is that, actually, scientists can't decide either.
What we know is that viruses are very, very ancient,
they've been important to human life for a very long time.
We've evolved closely with them and, of course, as we know,
they are capable of causing disease in humans.
But one thing scientists do agree on
is that viruses are on the boundary of life.
So, why don't we compare viruses to some organisms that we know
really are alive, like us, like humans?
How does viral RNA compare to human DNA?
Well, I've shrunk this genetic code for the coronavirus onto just one
single piece of A4, so all of those 30,000 letters that you saw on
the roll that JVT held up are now shrunk down onto this piece
of paper and to get it all on one piece of A4, it's absolutely tiny.
So...
..now let's see on exactly the same scale, what the
genetic code of a human being looks like,
and to do that, we're going to go to the human genome library.
And here it is. It's absolutely enormous!
In total, we've got 118 books here,
and every book has 1,000 pages.
So, just to give you an idea...
WHISPERING: Oh, my God!
..if we open one of these up and I get my little Handycam here...
..you can see again, that we've used exactly the same
writing that we used, and again, that writing is really, really tiny.
So there are a total of three billion letters
in the human genome - that's 100,000 times more than we saw
in the coronavirus genome, and if we were to turn this
into digital information, it would take up about three gigabytes as a
normal electronic file.
So this just shows you exactly how simple viruses are.
And their simplicity is part of the key to their success.
So how does something so small and so simple
take over and make us so sick?
Well, in order to understand this in a little bit more detail,
we need to go inside the cell.
We're now going to imagine that the cells in our body are a factory,
and in order to get in, we need to go through this security door.
Now, the cells of our body have lots of doors on their surface
and it's a way for different things to get in and out of the cells.
But in order for things to get into the cell,
they need to use a special key.
I'm going to see if this key will open this door.
And we're in!
And now, we're inside the cell factory.
Now over here, we have the boss's office.
This is like the nucleus of the cell where all the genetic information
that our bodies need to produce new cells and proteins is stored.
And over here, we've got the cell factory, and this is like the
ribosome of the cell and this is where all the proteins are produced.
So if our cells are working properly, what should happen
is the instructions go from the boss's office, across the
factory floor, to the cell factory here, and the instructions are
given to produce the products that our bodies need to build and repair.
For example,
we might need a spanner to repair cells, to repair muscles or bones.
Or, we might need enzymes like this that can break down
things in our body that are no longer required.
And this is how our cells work when everything is normal
and we're happy and healthy.
But what happens when a virus infects a cell?
I would like another volunteer from the audience, please.
Erm, in the blue T-shirt here. Why don't you come down?
What's your name? Tyler. Hello, Tyler. So, congratulations.
You have just volunteered to be a coronavirus particle! Thank you!
LAUGHTER
So we're going to make you look like a coronavirus particle now.
The first thing we're going to do is give you a protein coat.
So this protein coat is on the surface of all viruses,
including coronaviruses.
Now the other thing that a virus needs, of course, is its RNA,
its genetic information here. USB stick.
Thank you.
But what else does coronavirus have on its surface
that's really important?
Shout out if you know.
AUDIENCE SHOUTS SUGGESTIONS
Spike, yes! Somebody said "spike". You were exactly right.
So have you got any spikes on your coat?
Yes, you have. Right.
That might come in useful later.
But we're inside the cell.
And we've got a virus inside the cell. This isn't what we want.
Come on, out, out, out through that door. Come on.
We don't want any viruses inside our cells. Out you go!
And we're going to lock our virus outside.
FAINT LAUGHTER
So now, of course, we're inside, the virus is outside
so we should all be safe, of course, shouldn't we?
Well, maybe our volunteer, our virus, can get in?
So, our virus over there, our coronavirus,
do you want to see if you can get in through the door?
DOOR RATTLES
FAINT LAUGHTER
LAUGHTER
Well done. He's done it!
Well done.
So that was difficult, Tyler,
but you did manage to get in and how did you manage to open the door?
With the spike protein. Exactly.
So the spike is the key to opening the doors on the cells.
But the doors that are opened by the key
are specific for the coronavirus,
and not all cells have the right door or the receptor on their
surface - they need that matching lock. Now...
..what does the virus do now it's inside the cell?
Could go to the boss's office. But what do viruses really want to do?
AUDIENCE SHOUTS SUGGESTIONS
Yeah, they want to take over and replicate
so let's go back over to our cell factory.
And our coronavirus is going to insert its own genetic
material into the cell factory.
Now, let's see what the machine's going to make this time.
What's the first thing to come out, Tyler?
An envelope.
A USB.
Yeah. So we've got some more genetic material.
Another spike protein. Some more spike proteins. And what else?
Right. And now we've got some pieces of the protein coat from the virus.
So we're starting to make all the different pieces
we need for the virus to make copies of itself. And now we can see, OK.
OK, I don't think this is what's meant to happen.
Come over here with me, Tyler. I'm not sure what's going on.
Come over here. We've got more and more pieces of...
BANG!
..that protein being produced by the cell.
And our factory is in big trouble.
Our cell factory has just exploded, and this is not good for us
because all of those pieces of virus have now been released
and now go and infect new cells, and what does that mean?
We've all just contracted Covid-19.
Tyler, thank you so much for your help. You did a great job.
Go back up.
I'll take your coat.
OK. So what viruses do to us
depends upon the types of cells that they can actually break into.
And that's often determined by the shape of the key they use.
And here is a model
of the SARS-CoV-2 spike protein,
this red piece here.
And that is the specific shape
that allows it to bind onto this piece here.
And the piece I'm holding, the blue piece,
that's an ACE2 receptor
that sits on the outside of human cells.
But those receptors are most common
in the lungs and in the airways.
And that's why SARS-CoV-2
causes a primarily respiratory infection.
Children have fewer
of these ACE2 receptors than adults.
And it probably explains why the disease is more serious in adults.
Viruses can seem like pretty nasty invaders
but we do have an immune system
and that immune system can fight back.
Katie.
So our immune system is made up of lots of different organs
and cells and proteins, and it's what
protects our bodies from infection with bacteria and viruses.
The thing about our immune system is that if it's running smoothly,
we really don't notice it's there.
The first line of defence in our bodies against bacteria
and viruses coming in, is actually our skin.
And the skin forms a physical barrier that stops
everything on the outside getting inside our bodies.
But of course, there are weak points in that -
entrances into our body, like our mouth and our nose.
So we have a second line of defence inside our mouth and nose.
Does anybody know what that is?
Snot!
Did somebody say "snot"?
That's right! Bring on the snot!
Now, I'm going to need another volunteer to help me with this.
Does anybody want to come down and help me?
Erm, in the hat up there. Would you like to come down?
APPLAUSE
OK. So you go and stand down the other side for me.
OK. What's your name? Isaac. Hi, Isaac.
Right, what we're going to do here
is use our nose to look at how much snot the average adult
makes in a day.
So we've got a range of beakers here, going from very big
down to very small.
I want you to try and guess how much snot
the average adult makes each day. What do you think?
Erm, the big one. So you're going for a big one? OK.
Pick the one you think is right,
and if you put it underneath our model of the nose
and we switch on the snot, we should find out.
So, let's have another countdown.
ALL: Three, two, one!
WHOOSHING
Oh. It's coming out pretty quickly.
Is this going to be the right size? What do we think?
It's still going, Isaac. I think you might need another beaker here.
Do you want to get ready with another one?
Right, swap those over. Excellent. Yeah. That's it.
Well done. OK. Should be enough now. Those are our two biggest beakers.
That's it.
Is it stopping? No. Quick, get ready with another one!
Well done. Excellent. Keep going!
A lot of snot!
LAUGHTER
Go on, we might as well do the tiny one now. We've done all the others!
Thank you, Isaac.
So it turns out that all of them
hold the entire adult output of snot for a single day!
Isaac, thank you so much!
So as we've seen, the average adult produces around two litres of snot,
or to give it its proper name, mucus, every day.
But actually, when we're well, most of it isn't in our nose,
it remains in our airways and it has a really important role there.
It's there to trap anything that comes into our bodies
and stop it getting into our lungs.
So to have another look at this in a bit more detail, I'm going
to need one more volunteer.
Who wants to come down and help me?
In the golden top, there. Would you like to come down?
What's your name? Marta. Marta? Hi, Marta.
Right. So, we're going to have a look now at what happens
when viruses attack our airways.
And we've got a demonstration here of the inside of our airways
and now, it's snot-free, so there's no snot in our airways.
We've just got the simple lining of our lungs and nose.
So I'm going to give you these viruses.
We're going to throw these at it and see what happens.
Go on!
And another one!
Excellent!
So now you can see, when there's no snot in our airways,
these viruses are able to stick onto our airways really, really well.
So let's see what happens
if we line our airways with snot.
Have another go!
OK. Are you ready for this?
OK. Let's have another go now
and see what happens when we try and get virus in.
Try again.
Ohh!
APPLAUSE
Well done! Ohh!
APPLAUSE
So now what you can see is where there's snot,
it makes it much harder for the virus to bind on.
Where there isn't any snot, you can
see that they're still able to stick.
And snot's absolutely amazing because it contains special
antiviral and antibacterial enzymes which can destroy them.
Now, I bet you'll never look at snot in the same way again!
Thank you very much, Marta, for your help!
Now we've seen how wonderful snot is, but our immune systems
also have a search and destroy army of cells and proteins.
Now, the first part of this, you've probably heard of -
the first component is antibodies.
These are Y-shaped proteins that attach to the surface of the virus,
clump them together and stop the virus from being able
to break into our cells.
But of course antibodies can only bind
if they have the perfect shape to do so.
And of course, as we now know,
this is a problem because viruses
have all those different shapes that we saw earlier.
So, how do our bodies create millions of antibodies
that are exactly the right shape to combat a new disease
and new virus that we've never seen before?
Well, it all starts with a very simple game of chance.
And we're going to play that game now.
And I'm going to need everybody in the audience to be
a volunteer for this one. OK?
So you, in the audience,
you are all going to be a special type of white blood cell
called B cells and we have millions of them all over our bodies.
If we took all of our B cells in our body and lumped them all
together in one big clump, it would be about the size of our brain.
And B cells are absolutely amazing
because they all have
different-shaped antibodies on their surface.
Now, what I would like you all to do is look underneath your seats.
And hopefully,
you should all have a little model of an antibody under there.
So, if you've got your antibody,
could you hold it up in the air for me, please?
Great!
What we want to know is which one of you has the right antibody to
attach to our specific virus?
So, here is our target virus.
And what we need is the antibodies to bind onto it,
so we've made a big one here.
And we're going to now play a game. Over to you, Katie.
Great.
And the shape of this spike protein is going to be exactly the same as
the spike protein that we saw the virus use
to get into the cell earlier. So what we are going to do is
I would like everybody in the audience to stand up, please.
And we're going to find out
whether anybody here has got the right shape for our spike protein.
We're going to start on this side, on the red side,
so JVT, what's the first part of the pattern that people need to find?
Three red blocks.
So, if you've got three red blocks on your antibody model,
stay standing up.
OK, so everybody, I think, is still standing up at this point.
What's next, JVT?
So, next is two yellow blocks.
So if you haven't got two yellow blocks, sit down.
So we've lost a few people now.
And what's next?
Next is one green block.
So if you haven't got a green, sit down.
So what have we got on the blue part of the antibody model?
So now we need two blue blocks.
We're down to just a few final competitors. Oh!
And our very last piece? The very last piece...
..three purple blocks.
OK. So have we got anybody left? Yes!
We have a winner here in the middle. Come on down! Come on down!
Excellent. Turn round and face everybody!
What's your name? Sophia.
Right. So what we're going to do now
is we're going to take your antibody,
come round the side and have a look.
We're going to pop it on there and see if it binds perfectly
to the spike protein.
And yes, it does!
So you're the one
with the right antibody out of all those B cells.
Well done!
So as we've seen, Sophia's got the best antibody
to fit onto our spike protein.
But of course, just one little antibody like this
isn't going to be enough to fight off the virus infection.
There's one more step in the process that needs to happen.
Now, THIS is the model of a plasma cell.
It's another really important cell within our immune system
and its job is to produce very large quantities of antibodies
of the right type to fight off an infection.
So if you would like to take your winning antibody, please,
and put it into the top of the plasma cell here.
And then if you pull the lever there, and see what happens.
Pull it forwards towards you. Brilliant.
And now we've got lots and lots of antibody to fight off our virus.
So thank you very much, Sophia. You did a great job.
We have one more weapon in our immune system that can stop
viruses in their tracks and these are the killers in our bodies.
And this is actually my area of expertise in research -
killer T cells.
So antibodies are really good at going round our bodies and
mopping up free virus, but once the virus gets inside our cells,
only T cells can see them.
And killer T cells act as assassins, going round our body,
finding infected cells, and eliminating the virus
in a really precise and accurate way.
So we've got this amazing video here that shows exactly how this
happens in real life. So in the green, you've got a T cell.
It goes around the body with these finger-like protrusions on its
surface, and it's actually feeling the surface of the host cell,
looking for any indication that this cell might be infected with virus.
And if it finds that it's infected, it attaches to the
surface of the cell, makes holes and injects enzymes
and poisons to kill the cell.
This destroys the cell and everything in it,
including the virus.
The most important thing about our immune system
is its incredible ability to generate memory.
This means that once it's seen a threat like a virus once,
it's incredibly good at remembering how to attack it.
And THIS is the key to vaccines.
Vaccines train our immune system to recognise virus and to
produce the right antibodies and T cells to fight off the infection,
and this is something we're going to explore in the last lecture.
Thanks, Katie. That was a really fantastic description of what
viruses are and how they get in, and how we fight back.
And tell me something, how did you feel
when you knew for the first time
that the AstraZeneca vaccine was going to make antibodies
and help us on this journey we've been on?
Oh! I think more than anything,
I just felt incredibly relieved that the vaccine we'd spent
so long and put so much hard work into,
actually worked, because there's
never any guarantee when you make a new vaccine, that it will work.
So it was a big relief.
And tell us, what are you working on now in the lab?
So I've been working on malaria for a very long time, the world
desperately needs a new malaria vaccine.
And I hope that one of the things that will come
out of the Covid pandemic is that we can make
vaccines for diseases like malaria as quickly as we've been able to
make them for diseases like Covid.
That's brilliant. Thank you so much for joining us this evening.
Thank you. Thank you.
So now we know what a virus is,
how big it is,
how it can get inside,
and how we fight back.
Let's turn our attention instead to how we know
when somebody's been infected with a virus.
Because that's quite important, firstly,
if we're going to treat them, and maybe also if we're going
to keep them away from other people, so they don't spread it.
So let's talk about diagnostic tests.
But really, if you're going to talk about diagnostic tests,
then what we need is a virologist!
And our next expert this evening can help us with that -
it's Professor Ravi Gupta.
Thank you.
Hi. My name's Ravi. I'm a virologist as well as a hospital doctor.
And I've spent the last 15 years of my career trying to understand
HIV, but also improve treatments worldwide, and most recently,
we achieved the world's second cure of HIV in the so-called
London patient, or Adam Castillejo.
Since then, of course, the coronavirus pandemic hit
and we dropped everything to work on this new disease, and even now,
my team is working on the omicron variant
and trying to understand why it's spreading so fast.
From my point of view as a doctor,
the first thing we need to know when treating HIV is, of course, is
the patient infected? And for that you need a test, of course.
Now, designing tests depends on where that virus is sitting or
residing or replicating.
In the case of HIV, this replicates in white blood cells,
as we know, and so we do blood tests.
Now, SARS-CoV-2, of course, replicates or infects
cells in the respiratory tract, either the lungs or the nose.
And for that reason, we've got a giant nose here
and it's a replica of mine, apparently!
So we're going to take this apart
and show you where SARS-CoV-2 is actually replicating.
OK. So, hope you can see here
that most of the nose is actually inside the head,
the part inside, the soft part of the nose is actually very small.
And the virus, really, is sitting way back there in cells that
express the receptor ACE2, and so you can imagine,
this is not easy to test for with a swab.
And I think to demonstrate this, I am going to need a volunteer.
Oh. OK. How about you in the first row?
Hello. What's your name? Helena. Helena.
Thanks for joining us, Helena.
Now, JVT, please can I have a swab?
Don't be afraid, it's quite large.
But this is my nose, it's going to hurt me, not you.
Thank you very much. Right.
Let's just imagine now
that this individual was infected yesterday.
OK? By someone else who was positive.
We're going to try and do a test at day one,
so let's see if we can find any virus.
Would you like to take that for me?
And then, just put it into that nostril,
you're going to be pushing it forward, that's it.
Pushing it...oh, that hurts!
Keep going, keep going.
Until you feel some resistance.
Just twist it round, gently. There you go. All right.
And then you can take it out.
OK.
Oh, what do we have here? Right, there's some virus on there.
So that's day one.
Right, the person at day one is probably not feeling too unwell,
they're probably going about their daily business,
but there's some virus in there, as you can see. What about day four?
So day four, the person may be feeling a bit unwell,
cough, some fever.
Let's test at that time point and see what we find.
OK. So, same again.
Let's try and get more virus out this time. Here we go.
There we go. Right, two hands, I think.
Very good. All the way to the back.
So, remember, you need to go quite far.
And twist it around. OK.
Let's withdraw that, gently.
Fantastic. Wonderful. Thank you very much.
That's a day-four sample
and you can see there's quite a lot of virus on that swab.
Not what about by day ten?
By now, the person's feeling better, maybe completely well,
and may still get a test because, of course,
people get sick at different stages.
So let's see what happens at day ten.
Let's repeat that swab here.
OK. Big twist. And let's pull that back.
You're very good at this.
Right. Fantastic. Thank you very much.
Right, let's pop that on there. All right. Thank you very much.
That was excellent swabbing!
So what you can see from this experiment is that
when somebody's infected,
virus builds up in the body,
and then, as they get better, it clears again.
And on the day-one swab,
there's a fair bit of virus
but on the day-four swab, there's a lot of virus,
and on the day-ten swab,
there's not very much at all.
And this is important in two ways -
first of all, it's important
in terms of how the diagnostic
tests perform, and also, as doctors,
when we get a specimen from a patient and it's positive,
we also need to think about when that specimen was taken
compared with when the patient first got ill with symptoms.
Because it might change the result, you can see that.
OK. So, we have a situation where on day one, you may not have very much
virus present but you really need to know if that person's infected
because they would then isolate and stop spreading this virus.
So it's really important to have an incredibly sensitive test.
So the gold standard that we have at the moment is something called PCR.
Who's heard of PCR?
Fantastic. Right, it stands for Polymerase Chain Reaction.
And this has been around for more than 40 years, and the secret
of this is the fact that it is trying to identify bits of
the genetic code of the virus, it's not looking for the spike protein or
any other bits of structure of the virus, it's looking for the code.
What we're going to look for when we're testing is a short signature -
a signature that's only a few bases long,
something like a genetic fingerprint. So...
..we know what the sequence is going to be of that fingerprint
but we need to find a way of fishing that out of a sample
and the sample is in this bucket,
the genetic material from viruses and bacteria
from our nose are all in there together,
and we need to find a way of fishing out SARS-CoV-2 but nothing else.
And that requires us to understand
another concept, which is base pairing.
Now, base pairing is something that we have in our genetic code
and that's how we get double-stranded DNA or the DNA helix
and I will show you how that works because up here,
looking at our target sequence of SARS-CoV-2, we can add complementary
bases so the A pairs with the T,
and, for example, a G pairs with C. OK?
So based on that fact, we can design these things called primers.
And primers are really just types of bait, in a way.
We are using our knowledge of the target sequence to design
something that will help us pull that out.
So what we are going to do now is use this primer, OK,
to fish out SARS-CoV-2, and nothing else.
And so this should recognise
a complementary sequence in that bucket.
So we are going to have to untangle a few things here.
It is Christmas so there's some tinsel there. Right. So...
..as you can see, using my primer,
I have been able to fish out
a sequence and it looks suspiciously like the SARS-CoV-2 sequence
that we have on the board.
So let's prop this here.
And you can see that, hey presto,
we have pulled out from a mixed bag of different pieces of genetic
material, a SARS-CoV-2 specific sequence,
and of course, it comes with the primer attached
because that's how we fished it out.
So that's the first step but this really hasn't helped us, has it?
All we've done is fish something out that we can't see,
there's only one molecule there.
And we need to make many, many more in order to be able to detect
it with modern technology, so we're going to have to do something.
Hm, and this comes back to the polymerase that I mentioned earlier.
So, I think we're going to need a volunteer for this.
Let's go to this side, in the red jumper. Come forward, please.
Right. What's your name? Alexandra. Alexandra.
Alexandra, everybody. OK.
Right, you're going to become an enzyme, you're a protein,
like a little robot in a cell.
You're going to add
little letters or shapes onto this strand
so that they match up, all right?
So what I'm going to ask you to do is just find shapes that match
the ones that you've got here. And just pop them onto the Velcro.
OK. Let's see you do the first one. OK.
Excellent. As Alexandra does this,
I'm just going to explain the type of polymerase we use because
we don't just use a standard human one, we use a polymerase that's
derived from special bacteria that live in really high temperatures
and that were first isolated in Yellowstone National Park
from a bacterium called Thermus aquaticus,
and the name of the polymerase is therefore TAC.
Now, in order to make more of this,
we are going to have to find a way of putting our primers back on
because remember, the primers were the reason this worked
in the first place.
Now there's nowhere to put those primers on at the moment, is there?
So what we're going to do is break those two apart.
And the way we do that is with heat.
So, can we have some heat, please?
It's going to take a temperature of something like 95 degrees in order
to break the hydrogen bonds between these two strands, and once
we reach 95 degrees, we're going to be able to separate these two.
As you can see here.
You've now got two strands and, lo and behold,
the primers can attach, but before that happens, we need to drop
it down to 60 degrees, please,
because otherwise these primers won't bind.
So we're down to 60. Let's put the primers back on.
As we can see here. Right.
Now, you've got the ability for our polymerase friend here to add
more bases, so would you like to add some more on?
So.
It's amazing that,
a polymerase from a bacterium in the middle of a hot spring
in the middle of the US,
now underpins the great majority of our molecular biology
and a lot of our scientific advances would not have been possible
without polymerases, and I cannot stress that enough to you.
It's an incredible achievement.
All right. Thanks very much for that. You were wonderful. Bye-bye.
OK, folks.
So we started with one strand and we ended up with four here,
after a cycle of PCR.
The number of strands will double each time, so if we were to heat
things up again, to 95 and cool down again, we would get eight strands.
And then, after another round, we'd get 16, and then 32.
Can anybody tell me
how many we would have after 30 rounds of this PCR cycling?
You can shout out.
A lot! A lot! That's correct!
500 million. A million.
A billion?
AUDIENCE SHOUTS SUGGESTIONS
500 million. It's about a billion. OK.
So you'd get a billion copies after 30 rounds of PCR - that would take
you around three hours.
That's incredible amplification and it's quite easy to detect a billion
particles, and that explains to you why PCR is so sensitive because
it takes a tiny amount, makes lots of it, and then you can detect it.
Thanks, Ravi.
So, now you can see that, you know, use of PCR in the Covid pandemic has
been an absolute revelation to us
but it's an incredible technique that we're now using
to diagnose lots of other diseases,
including TB, HIV.
We can use PCR at the scenes of crimes to detect what's gone on.
We can use it to actually tissue type for organ transplants.
And PCR is becoming quicker and cheaper as the years go by.
But as you saw from Ravi's demonstration,
it's still quite complicated.
And it still takes three hours
to make those billion copies.
It's not the quickest thing in the world.
What if we need to diagnose people faster than PCR?
And maybe in a simpler way?
Can you think of another test that works for that? Give it a shout out.
AUDIENCE: Lateral flow!
Lateral flow. What's a lateral flow?
Ah! Yes, all right. Ravi!
Lateral flows. OK. All right.
So who's taken a lateral flow? You all know what it is.
Right, of course, everybody knows what it is
because you had one to come in here, didn't you?
OK, right. So here, to demonstrate this
is a giant-sized lateral flow device,
generated by our colleagues here at the RI,
and it even has a barcode that works,
and it has a test strip with a C on it that means control,
and this means that the test has worked once you put the sample
through at the top. And the T, if this goes positive,
it means there's coronavirus in the sample.
So I think we're going to need a volunteer for this.
Someone in the middle now.
I'm trying to stay away from the red jumpers! OK.
Red jumper, in the middle.
Come over this side. Right.
What's your name? Max. Max.
Max, thanks for coming down.
Right, you are going to demonstrate this giant lateral flow test
to everybody.
Right, so what I'm going to do is give you a sample. Here.
And I'm going to ask you to pour this into the sample well, here.
Normally, this would be liquid but it's balls at this time. OK.
Right, and we're going to count down from three.
ALL: Three, two, one. Go!
RATTLING
So as you can see, the control line has come on
but the test line hasn't, and this shows that the test has worked but
there doesn't seem to be any virus in there,
so this is a negative test.
Right, Max, now we're going to give you a second sample, OK?
You did really well the first time.
Let's see how your luck is running tonight.
Let's pour that down through the sample well. Go!
RATTLING
Excellent. Thank you very much, Max.
As you can see, this is now a positive test result
because the test has worked and you have the red lights coming on -
in other words, the test is positive.
So this is a sample that had coronavirus in it.
Thanks very much for coming down.
OK. So we've seen a positive test result
but how does this thing actually work?
Let's look inside.
Imagine these balls representing virus particles.
They're covered in spike protein, aren't they?
They're going to pass through the test.
Now, on this red line, in a real lateral flow device,
we have immobilised or placed antibodies to spike,
and you saw how those were generated and how specific
and tightly they are bound, in Katie's talk.
So those antibodies are placed along there and as the spike goes
through, it will bind to the antibody and trigger a colour
change, and that's how the lateral test works in reality.
Ravi, that was fantastic and I've always wanted to know what
was inside a lateral flow device
and finally, you have explained it to me. So...
..as you can see,
we've got one test that's super-duper sensitive,
but takes a long while.
And we've got the lateral flow tests which aren't quite as sensitive,
but are really quick and really practical.
And that's one of the things in medicine
and indeed, in controlling this coronavirus pandemic -
you have to choose the tests
that fit the purpose.
And lateral flow tests, we all know, we've all used them, they're very
quick and simple, but the really accurate ones
are the PCR tests.
And perhaps that now explains to you why the advice is that if you
have a positive lateral flow test,
you still need to go and get a PCR.
So is there a way of getting the best of both worlds -
something that's quick like lateral flow tests,
and something that's as sensitive as PCR?
Now, early in the Covid pandemic,
our hospital was overrun by hundreds of patients with symptoms,
and we needed a really quick test that could be
done near the patients, to give a really quick result
that was accurate, because if we got it wrong, people could be
transmitting coronavirus to each other within hospital,
which is a really dangerous scenario.
So there was immense pressure to find such a system.
And during my HIV work, I had used a test developed by an inventor, and
here to explain this test is the inventor, Dr Helen Lee.
Hello.
Helen, welcome. Thank you.
Could you explain to us what the original purpose of the machine was?
Well, originally this machine was to test for HIV in Africa,
in the villages.
And we had to check whether the HIV treatment was working and
also whether the babies that are born to HIV-positive mothers
is infected or not.
And we take the test to the patient rather than the other way around.
So, Helen, can you explain to us how this works? OK, it's very simple.
I'm sure you have all done a lateral flow test and have seen this
before, right?
A tube with a swab in, yes?
So what I have done is that I have
transferred with a pipette 300 microlitre
exactly into this separate tube, so you can see I have this cartridge.
I put it in here. And then the second cartridge I put it here.
And the third one I put it here.
But you can see, I cannot put it in the wrong way and now I am
going to put the detection cartridge in.
And this, in the NHS sites, some of them call it the ballerina
because it dances and twists.
And you'll see. So then I put this sample here. Now, I'm ready.
All I had to do to load it is this simple.
OK. So now I just close the lid and then what happens is that this
particular tablet will prompt me to do the next thing.
So now I just say start.
It's a combination of PCR and lateral flow.
It amplifies like PCR but at a constant temperature and so
the target also gets to be amplified to billions of copies, but
then the detection is visual, just like a lateral flow.
If it is negative, it has only one line.
That shows that the chemistry worked.
And if it's positive, then you have two more lines, showing that
you have Covid.
Can you tell us then what the benefits are of this machine?
Well, the main thing is that it is accurate. It's rapid.
It gives you the results in about an hour.
Can it be used for any other viruses or other diseases? Yes.
We just developed a multiplex test which detects Covid plus flu A
and flu B, so it is a multiplex test.
It's going to be shortly in the hospitals, in the care homes
and even in some schools.
Fantastic, so that's incredible, you've got a test that can do
multiple different viruses and tell
you fairly quickly what the diagnosis is.
That's incredible for a machine that was developed initially to test for
HIV in resource-limited settings, where there was poor access to PCR.
Thank you very much.
Thank you.
Ravi, what a tour de force on diagnostics.
If I asked you two years ago whether you thought we could get to
where we've got to now with diagnostics for coronavirus,
what would you have said to me?
Well, I wouldn't have believed you, because of course to bring
tests from development all the way through to clinical use takes
a very, very long time, a lot of validation, a lot of studies.
And so the rapidity of this has just been incredible.
I'm really stunned at how
many different tests we have of high-level accuracy.
Thank you so much, Ravi, thanks for being with us this evening.
Thank you very much.
We've seen that rapid testing can increase the quality of
patient care, but could there be
even faster ways of testing?
Let's bring on our next set of guests.
Mark and Scott and Jodie and Millie.
What we've got here is we've got four Christmas stockings
with four different things.
Actually, the things are on the backs, on the little sensor
panels, and in two of these Christmas stockings we've got old
sweaty socks.
But one of the old sweaty socks was worn by somebody who had Covid-19.
There's no Covid-19 around this evening, please don't be
afraid, but the smell of Covid-19... Have you ever smelled Covid-19?
..might still be on one of the socks.
And on the other two specimens we've got wound specimens and one of those
wound specimens is infected with a nasty bacteria called Pseudomonas.
Pseudomonas can be quite serious for patients who've got damaged
immune systems. And the other swab has got nothing on it.
It's not infected.
And so what we are going to do is see if our little friends
here can actually find these infections for us.
So let's start with Covid.
Which dog have we got for Covid? This is Millie.
So Millie, this is Millie.
Millie's been specially trained to sniff out Covid.
Over to you , Mark.
Millie.
She's found something. Yes, good girl. Very good. Good girl.
Was she right?
Yes, she was. Well done. Jodie. Jodie, here.
Right, Jodie, you've got an act to follow now. It's your go.
Jodie is looking for Pseudomonas.
Hey, good girl. Good girl.
So there you have it.
Dogs that have been trained to sniff out infectious diseases.
Now, I hope we are about to be able to be joined by Dr Claire Guest
online. And here she is. Good evening, Claire, can you hear me OK?
I can indeed, good evening, everyone. Thanks for joining us.
Now, you know a lot more about using dogs in medical detection
than I do, so I'm just going to ask you the questions.
How could these dogs be used in the future?
Well, what you've just seen is the biosensor with a fluffy coat
and a waggy tail and as we know, dogs have been used for many years
keeping us safe by finding drugs and explosives.
What the dogs have done here is found the odour of disease, so when
we have a particular disease or condition our odour changes
and the dogs with their incredible sense of smell can be trained
to detect this and warn us.
So we can't smell these diseases but the dogs can? Absolutely.
They've got 350 million sensory receptors dedicated to olfaction.
Now, I don't know if anyone would like to guess but us humans
have got five million, which means we can smell a teaspoon of
sugar in a cup of tea.
These dogs can smell a teaspoon of sugar in the volume of water held
in two Olympic-sized swimming pools, a quite incredible sense of smell.
And the dogs are really happy to put this nose to work to find disease.
For example, Millie the Covid dog, she could go out now, she
could have screened every person as you came in this afternoon.
So these dogs, because they are very rapid, they could screen
hundreds of people at a time. Thank you, Claire.
Thanks for joining us this evening.
And thanks to Jodie and Millie and thanks to Mark and Scott.
So I think you've seen in this lecture just a first glimpse
of how the pandemic has really been
transformed by scientific achievements.
And in the next lecture, we're going to think about how these
viruses spread, why some humans spread them better than others and
what we can do to stop them. That's for next time.
Thank you for being such a great audience.
I hope you've had a good first lecture. Thanks for joining us.