So, first of all, thank you very much for coming. It really is amazing to see so many people here.
And it's great that you're interested in what we're doing. It's like this in the first week of Michaelmas term, in the first.
And most of you are awake as well. OK, so I'm going to start from where Andrew left off and then take things in a different direction.
I'm going to talk about what we've come to call active matter, but really, this is just physicists doing biology.
We're looking at all sorts of different systems, we're looking at cells, we're looking at bacteria,
and we're looking at these molecular motors that Andrew talk to you about all the way up through to larger biological systems.
But these are too hard for us.
So we prefer to stay and try to understand these tiny things and in particular to concentrate on the sort of things that physicists ask.
So let me start with a sort of really broad overview of the big questions,
and they're really the big questions which are underlying Andrews talk as well.
And I think the first one of these is how do we work?
Thinking of ourselves as engines, how do we actually manage to do all the things we do move around,
but also breathe and reproduce cells and so on and.
In the old days, the answer was you have muscles, right, and you wave your muscles around and you move.
But now we can ask a deeper question than that because we know we're made up of cells
and something must be happening inside the cells to get all these life processes going.
For example, to actually make them muscles move and to move things around in the cells.
And Andrew showed you how that's done. That's done due to these molecular motors.
And I'm going to show you again, this beautiful movie because I like it so much.
It's just so amazing. The first time I saw it, I said silly, isn't it?
But it's not. This is really what's happening inside our cells.
First of all, the cell has to lay down tracks for the motors to move along.
That's because we're tiny here with nanoscale. And so there's a lot of Brownian motion.
So any motor trying to just move around not being tied down is going to just get buffeted away and not be able to get anywhere.
So you need to put down tracks and the cell is able to make these tracks and then to dissolve them again due to careful,
really complicated and clever chemistry.
And then the motors move along the tracks, carrying around the various proteins from one place to another in those sort of backpack things.
This thing is like its backpack, which is the vacuum. And Andrew showed you how we're trying to make these molecular motors, and it's hard.
The cell is amazingly good at doing this and then that's just making one of them.
Also, you've got to control this system, it's it's a very complicated control problem, the cell has to work out, work out how to put down the tracks,
where to put them and then to organise the motors and the vacuoles which carry things around and then work out
how many motors it needs to pull things around and where it needs all these different sorts of proteins to go.
It's a mind blowing problem in control theory, and Andrew showed you, even though he's doing these amazingly well, these experiments,
it's hard to get anywhere near building one of these molecular motors that lots of them working out how they all work together.
And so that's a really big problem. And that's one of the really big problems we want to understand because nature has evolved to do it very well.
And if we learn how it's done, we'll be able to use these things to actually make machines and help in medicine.
Just to show you a real picture rather than the computer simulation.
These are these little heads here moving along the microtubule, this is like microscopy where you can actually see these things.
So Nature sells its machines is one big question, the other one is how do you make these motors in the first place?
And again, we heard about this. And as an example, let's look at this.
There's a thing called the bacterial flagellum motor, which turns.
The flagella of a bacteria, it sits here across the cell membrane, and it looks pretty much like this.
Each of these different bits is a different protein and the sort of length scale we've got here is about 30 nanometres.
How'd you make it? Has anyone make it? I mean, this is a computer graphics because it's a nice movie showing you how this thing might be made.
Presumably it's built up sequentially. But you've got to take all these different proteins and you've got to put them together in the right order.
It's called self service self-assembly, it's active self-assembly,
because you're putting in energy, things are working out of equilibrium the whole time.
You know, and it's just slightly mind blowing, how anybody how nature manages to do it, we can't do anything like that.
We don't even understand how much simpler systems are put together.
And we would like to understand it because we would like to be able to make motors this sort of size.
OK, so that's sort of the big picture. It's the sort of picture that experiments like Andrews are starting to address.
I want to go in a slightly different direction because we're theoretical physicists and to us,
one of the really exciting things about this sort of system is that this active matter, biological matter is out of equilibrium.
It's out of thermodynamic equilibrium and it's meant to stay out of thermodynamic equilibrium because otherwise you're in a bad way.
Now you remember, presumably many of you sitting in this room that you learnt about the Boltzmann
equation and you learnt about what happens when you have lots of particles.
That's a statistical physics and how an equilibrium.
You can tell that you've got the Boltzmann distribution describing things like the velocity distribution of a gas.
That's an equilibrium system. That's what happens to a gas when it comes to thermodynamic equilibrium.
And when you were an undergraduate, you learn a lot about equilibrium and not about much else.
But what happens out of equilibrium?
What happens when I take a system like this and I put together lots of active particles, lots of cells or lots of molecular motors?
And so I'm doing statistical physics, but I'm doing statistical physics of a system which is meant to be out of thermodynamic equilibrium,
which is continually taking energy from its surroundings, usually in the form of ATP and using it to do work.
And that's the question that we're going to ask, and we're going to end up looking at topological defects.
And we're going to end up finding topological defects in biological systems.
So what sort of experimental systems have we got?
I'm going to tell you about this experimental system, which is a very beautiful one that's been around about five years now.
These are these molecular, these it, so these are these microtubules,
these tracks that the molecular motors walk on and the group and Brandeis managed to isolate these tracks.
So basically they got a big test tube full of these tracks and then they put in these molecular
motors and these are two headed molecular motors and the motors walk along the tracks.
So these little bits here are the feet, but they're attached to two different motors.
These voters have a direction to them.
So if you've got two tracks and the voters are all working in the same direction, nothing much is going to happen.
But if this head is moving in that direction and this one is moving in that direction, it pushes these microtubules relative to each other.
And what you're going to get is some sort of dynamics. So let's look what that dynamics looks like.
Takes a little bit to load, this one does. There we are, you can see the of white threads.
All these microtubules, and they're being pushed around by the molecular motors.
And you get something which looks like turbulence. OK.
It's not real turbulence, because here we're very small and large scales where you normally see turbulence, but it's chaotic motion.
Let's have a look now at putting lots of another sort of active system together.
These are bacteria that probably E. coli. So we've got lots of E. coli in a two dimensional layer.
And again, you get something which really looks like turbulence, you get patterns, you get patterns which are larger than the individual bacteria.
And if I plotted the vorticity field, which is basically where the flow is going this way or that way,
what you find is you get these regions of high vorticity, red goes that way and blue goes that way.
And this sort of scale here is about 10 bacteria across.
So you're getting some sort of collective turbulent motion from these individual active particles.
You seen that in other places as well. I think the next one is these are cells, these cells on a petri dish or two dimensional layer of cells.
And if the cells just they do that, they sort of tend to move around the dish when again, you get these sort of swirling.
Motions.
And the reason I'm showing you lots of different systems is that I'm a theoretical physicist, and therefore it's hard to remember any one thing,
and we want one theory which describes everything because then we can cope and if we're lucky,
it might describe this as well, which, of course, of the beautiful patterns we see with starlings.
This is a bit different because it's in three dimensions.
They're moving in three dimensions, and they're not so squashed together as the other systems.
And then I like this one. This apparent is a dolphin, was it don't know seals are a seal.
I gave this talk in the Netherlands and they were very insistent that it was a seal and they know and it's not a shark,
you can tell because of the surfboards, right? I was not shocked. And this thing is trying to find its dinner, and it's having trouble.
And somehow that's some sort of collective behaviour in those fish.
I mean, this one's a bit different, but again, you're getting this collective behaviour, these active systems,
these living systems are behaving in a collective way in response here to some sort of perturbation.
And I believe it's not possible to predict this.
We don't know what's going on. OK, so this this is this is.
What I'm going to talk about, I can't cope with the sealed and the difficult things I would get.
OK? I wanted to try and understand this swirling state that you get.
You get it with the bacteria and you get it with these mixtures of microtubules and molecular motors.
And to understand it, I need to first tell you a bit about liquid crystals and topological defects that come out in liquid crystals.
So electric crystals are as they're long, thin molecules shape,
which is long and thin and at high temperatures, they just order random weather in order a tool.
They just point in random directions. If you call them down, they form a pneumatic state.
A democratic state is one where the molecules all point in more or less the same direction.
So there's what we call orientation or Lowder, but no positional order.
They're not on a lattice. The reason they do that is just then they increase their entropy, they have more space.
Now we know about this in Oxford, right, because of high temperatures in the summer.
You get an isotropic phase and at low temperatures in the winter you get a pneumatic phase.
These secret crystals are really important.
They are in all the display screens that have display screens work because of the way they interact with light.
And one of the problems, if you're doing display screens, is that you can get topological defects in these liquid crystals.
Places where the ordering wire this alignment goes wrong, they're called topological defects,
because if you want to untwist this, you actually have to move everything all the way out to infinity.
It actually mucks up the order everywhere. This shape here is called a plus a half defect, or I think we call this one a comet defect.
This one here is a minus a half defect. It's the only ones we're going to have to think about, OK,
places where the ordering goes wrong and normally what will happen in a in a normal
liquid crystal is that the plus two halves and the minus the halves behave like charges.
They move towards each other and they destroy each other because they want to minimise their energy.
You really don't like having these guys, and so they move towards and they destroy each other.
And if you're lucky in a perfect liquid crystal, they will inil out.
But in an imperfect one, what happens is they get stuck on basically dirt in the liquid crystal, and then they muck up how good they are as screens.
This sort of logical defects are all over the place.
Biology was until recently the only place they weren't really are meant to be important in the early universe.
There, certainly you would have seen as undergraduates their importance is crystal dislocations,
and a lot of the recent work in Hard Condensed Matter has been interested in these defects.
We wanted them to be in biology as well.
So let's go back and have another look at this, that's my suspension of my swimmers, this is the sort of state that you get.
And these things are pneumatic right there, long and thin, so you might expect some sort of pneumatic properties.
So we did a simulation of this and we asked, Let's have a look at it.
Let's actually look at the top of logical defects and see what they do.
So what I'm going to show you now is a simulation of this basically this sort of vorticity field with the topological defects on it.
OK, the red ones are these plus I have defects and the blue ones are the minus a half defects, and I think those guys are going to do the right thing.
They never did. The ones I want to look at, OK. They annihilate in pairs, which they're meant to do.
OK, but then just look here. They're created in pairs.
All right. I'll give you just pair to get in a minute.
OK, if you look carefully, you'll see them disappearing, which is what we expected, there's one there,
but the number isn't decreasing, and that's because they're also popping out and being created.
And that's what makes these out of equilibrium systems, these active systems, these biological systems different,
that you can have a sort of gas of these topological defects, which are continually being destroyed and then reformed.
It's the energy that you're pumping in, which allows them to be formed, and then what happens is in a passive system,
you know, by thermal fluctuation, you might get a pack, but then they'll destroy each other immediately.
What happens in these active systems if a pair is formed? They say they actually move because of the stresses on them because of this activity.
They move away from each other and in particular the plus a half once a motile and move quickly away.
And the minus a half ones aren't maritime time. They tend to stay there. That's just because of their symmetry, really.
Because these are asymmetric, they don't move anywhere. And so they're able to escape from each other.
And I think I've got a slide which shows the velocity field around these things.
This one here has a velocity field with two loops, and it moves in this direction.
This one here actually has a velocity field with six loops in it.
Let's look at the experiments again and see if we can actually see these things in real experiments,
let's look at these experiments where I had the microtubules driven by molecular motors.
And you'll see an arrow. Red Arrow after the plus a half defect, blue after the minus a half.
So these turn out to be defective.
I know it's I've got to still in a minute because it's really hard to see them until you've been looking at them lots.
But we will look at the dynamics. Basically, these things fold over and form defects.
You can sort of see that the three fold symmetry, sometimes at the minus one's.
And if it worries you, which I think it might, right, this is a still this is evolving with time.
These are the microtubules. They sort of bend over and they make this.
You can see that this thing has the shape of a plus a half defect.
And this thing has this shape. Of a minus a half defect.
OK, so people have looked at these, they've looked at their properties. They pretty much understand how this defects drive this active turbulence.
There isn't really a theory of what's going on here. That's still to come.
All right. There's an understanding, but there's not what theoretical physicists would call a theory.
So. Let's do the biology now, just in case there are any.
This is just just in case there are any biologists in the audience, I can never remember the right words,
the right biologists are really good at remembering things and they mind when you say it wrong, so I'm afraid this is the best we can do.
We're looking at generic properties here. I do my best.
So so. Two, two stories I'm going to tell you, if I've got time where we actually find topological defects in real biological systems.
And. Then in both cases, they actually do something.
They have a biological relevance. And this is all very new people only sort of.
Well, we found this stuff a couple of years ago.
OK, well, let's not even and some certainly the first part of the work I'm going to show you is is published.
And so it really is very new research and you'll see that these are really rather model systems,
but maybe these defects are important in real medical systems as well.
The jury is out. So I'm going to start with these bacteria, the cake, and these bacteria pretty obviously have pneumatic symmetry.
All right. We're going to look at how to write this name down this one Pseudomonas, which is one of the official sorts of bacteria.
These things crawl. I'm looking at them. They're meant to crawl if a move is going to work.
Yes, they will. All right. They're moving in a two dimensional layer on a surface.
This is the sort of thing you'd see prior to biofilm formation.
They pretty obviously look like this liquid crystals, they have pneumatic symmetry, they have this head tail symmetry.
They move by having little legs, so they sort of walk along the surface on these little legs, which pull them along.
OK, it's called twitching mobility, and it doesn't actually matter much,
but they do change direction, so their motion is pneumatic as well, moving in both directions.
OK, so maybe we can find topological defects in this system. I mean, the right shape.
All right. And there they are, these are the topological defects, the red ones are the plus ones which are moving the blue ones of the minus ones,
which are not self-propelled, they're only moving when the rest of the bacteria drags them along.
And just to check, because we do lots of modelling, we wanted to do a model of these.
So we did the very simplest model you can think of. We had a load of rods in our computer and we just gave them a velocity, so they moved.
And when they hit each other, we had a repulsive interaction so they didn't overlap.
So rods, which can't overlap, moving around.
This is what happens if you do that here with the rods, they're moving, they're repelled by the other rods.
And again, you can see the defects, the topological defects, OK?
You can get the computer to find those for you. Now, it seems a very reasonable question to ask.
You know, are they really like the topological defects we saw before that these are places where you know,
you can you can define the idea of a topological defect, but did the same thing as we are seeing as we're used to from the liquid crystals.
Are they the same in this simple model? And in the real bacteria and in the simulations I showed you to start with?
And so what we did is we measured the velocity field in all the different sorts of models and the simulations.
And here's the answer for the velocity field. This is what I showed you before around a plus a half defect, two loops.
Here is what happens around a minus a half defect, and you get these six loops.
This is what happens in that model of rods. Same thing, but it's a bit more noisy.
This is what happens in the experiments. Same thing again.
It's a lot more noisy because these are real experiments on real things, but for all the logical experiments, this is amazingly good agreement.
OK? You can see those six loops. So we're seeing the same thing.
This is really very strong evidence that we're seeing the same sort of thing in these bacterial layers and in sort of theoretical models.
OK, so the reason we got to this was that we,
as zoologist colleagues and people in zoology were interested in what happens when you have different strains of bacteria which are mixed together.
So the question was to mix two different strains of bacteria here blue and yellow.
But I'll tell you what those are in a minute.
And to see how they expanded because bacteria like expanding, that's one of their rationales for being is to invade places.
OK, so you put them on the surface and you look how they expand as they divide.
So they expand partly because they're dividing and partly because they're motile.
And to understand this story, you have to think of the hair in the tortoise.
OK, this is a hair in the tortoise story and the bacterial world. So the two different sorts of bacteria that were mixed together is, first of all,
the wild type Pseudomonas and what the biologists mean when they say wild type is ones that they haven't looked around with.
The way they mucked around with some of them is they made these things called delta pillage.
And what they did, though, is add more feet. So they did genetic modification.
So these things had more of these feelers. And so they moved faster.
So they had two populations. The brown population had this is the velocities that they had.
The brown population had high of high velocities and the blue population had lower velocities.
So I think I might have got the colours wrong, but never mind. These are the wild type.
These are the guys that just slow. These are the ones with more feet that are fast.
And the colon is expanding. In this direction.
OK, slogans at the top is the colony expanding. OK.
So this is very strong evidence. That the slower ones.
They start off slow, but then they expand faster. Exactly the hair in the toe Toy Story, these lines, everybody worries about these lines.
That's just because you have to move the stage of the microscope. All right. And there's no cheating.
You don't sort of wait in one of them to let men get faster. Yes.
OK. So why why are these slower bacteria moving faster?
This is more evidence for the same thing. All right.
The yellow ones are the first ones.
If you look at the edge of the colony to start with, the yellow ones win.
But later on, as the colony gets denser. Somehow, the yellow ones aren't there, and it's the blue ones which are spreading the slow ones and moving.
OK, so why we've got to answer why.
Well, this is a picture of the inside of the colony and experimental picture, and what you can see is you get sort of blobs forming.
And these blobs are stationary. The movie sort of stops when they become stationary.
You can see that the stationary blob says somehow you're getting blobs forming.
And it turns out that these blobs tend to be mostly made up of the faster bacteria.
Those blobs are places where the bacteria, instead of moving around horizontally on the surface form clusters, which are pointing upwards.
Places where they basically form pointing upwards.
Clusters which are stuck. We call it vertical ization, but at such a horrible word, I really didn't like saying it.
All right. Clusters where they're stuck, clusters where biofilms will start to fall.
And for some reason, that happens with the first ones, but not for the slow ones.
And so the fast ones get stuck in these sticking up clusters and the slow ones are left to expand.
So we've moved the question to how are these stacking up clusters formed?
And the answer is because of topological defects. What happens is that these plus a half defects by chance.
Two of them are moving towards each other.
Two plus a half defects moving towards each other form a virtual plus one defect and start moving around each other.
As they move around each other, a combination of energies and the momentum pushes these guys up so that they stick out of the plane.
It's a reasonably slowly moving towards each other, which would happen for the Slovak teria.
What happens is the defects come in. You get things standing up on end.
But there isn't enough energy to form you to really nucleating a standing up cluster.
They join together and they fall back down again. Whereas for the fast ones, what happens is you get this standing up cluster formed.
And then my simulation box isn't big enough, but then it keeps growing.
So the first ones confirmed the vertical clusters and the slow ones Kong.
This is a picture of it actually happening in a real system, but it's a bit hard to see.
Again. This is a real experiment. Very clever experiment you can just about see it happening.
And here is instead still of the same thing. Here is the region where they're standing up on end.
You can see they're the end of them or here, perhaps from the side, it's easier to see they're standing up on end,
and they tend to be the first bacteria which join together in these clusters.
So then we did another simulation just to really say the same thing, just to check.
We put fast and slow together. You can see the standing up clusters forming.
And you can count the number of fast and slow bacteria in these clusters, which is standing on end, which are stuck.
And you find that many more of the first bacteria in there.
And so that leaves the slow ones to be able to spread. And remember, what started off those clusters was the topological defects.
It's because you've got problems for defects in these systems that you can get this nucleation of of things which are standing up on end.
OK, so that's the hair in the tortuous story. What we actually did first, which was stupid, because it's much harder.
Was to look at topological defects in a different sort of cell in these eukaryotic cells, so these are cells which line your stomach.
Indeed, pretty much all the surfaces of your body, so they're meant to be in two dimensions, more or less.
OK. And what people do is take them out and cultured them and put them on petri dishes.
So you have two dimensional layers of cells.
Now, it's much less obvious that these things are anything to do with these pneumatics with topological defects because they're the wrong shape,
they're circular. So what actually happens here is what we did is we looked at these cells, and as they move, they tend to get pulled.
And so instantaneously they do have a long axis. So we took that long axis and we put a line along it.
And that made it look like a dramatic. And then we looked for topological defects.
And in fact, you can identify topological defects in these systems.
This is one of these +1 ones, and you can see that it's moving, which is what the plus sorry plus half ones are meant to do.
And you can measure the velocity field around it and it looks the same. And so these these guys really are topological defects.
One of my favourite experiments is this one.
What happened here is that we measured that we counted the number of these topological defects in one of these cell layers.
And then the experimentalist administered something called Blaby Statine to these cells.
And what bleb is starting is if you're a cell is basically a sleeping pill, so it puts them to sleep.
And so if they're asleep, they're not moving, they're not being active,
they're not behaving as an active system, and they're not creating topological defects.
So you expect the defects to slowly aneel out.
And that's exactly what they're doing. This is, the number of defects goes down with time because the cells have stopped moving.
Then you get to hear and what happens here is that the destruction is washed out.
So basically it's an alarm clock and the cells wake up again. If the cells wake up, then the number of defects starts to increase.
And you end up with, I think, quite nice evidence that the activity in these systems is creating topological defects.
So that's fun. Is there any biology going on here?
Well, what we found is a correlation between the position of these defects and places where the cells die.
So here's my cell layer. And what happens is this in these layers, you get cells which die and are pushed out of the layer.
This is a perfectly normal thing because new cells are being created all the time and you need to keep the density of cells constant.
It's called apoptosis. It's just dead cells being removed from the layer.
We found that the places where the apoptosis occurs is related to the position of the topological defects.
This is a biological result, so the correlation is not 100 percent, but it was pretty strong, strong enough that we believe it.
And actually, there's a mechanism why that might happen.
As a physicist, my thought was right topological defects are regions where everything's ordered in the wrong way.
That's a position of high stress.
And so it's sensible that this is why the cells get miserable and they die off and then they're pushed out of the layer.
It's sort of like that, but life is a bit more tricky.
And biologists and what my very clever biologist colleagues worked out was that actually what happens is if you do have regions of high stress.
A protein called Yap is expressed, and it's moved from the nucleus to the cytoplasm.
So this Yap thing is a chemical signal. And this is a chemical signal why cells die and you can show that at the top of logical defects,
because of the stress, the Yap moves from the nucleus to the cytoplasm.
And that's what kills the cells. And once they're dead, they're ejected from the monolayer.
OK, so I've shown you. To places where you end up with topological defects, actually doing something in biology.
They say it's only I think it was about 18 months ago. This was first started this research.
So there's an awful lot for biological systems out there to look at.
And that's what we're busy doing at the moment and in particular.
The reason we can do this research is because we have such amazing graduate students and postdocs here.
The people most responsible for this work is Ali and Ahmed.
But another list of other students, postdocs and colleagues that have collaborated.
And the other thing I'm going to say is that pretty much none of these people are British, and I think that's brilliant.
Theoretical physics is somewhere where people from all over the world can come to the
UK and we can be friends and we can give Connexions which are going to happen forever.
For example, Armin is from Iran. And that's one of the really nice reasons for being a theoretical physicist.
Thanks very much, Alison.