- Welcome back, for those
of you who've been before, welcome for the first
time for those of you who are coming for the first time. We've talked in previous lectures about the evolution of microbes, and in the last lecture, we talked about how microbes can make some really impressively large structures. Tonight, what I want to do is,
is go to the other extreme, and talk about some of the
really small structures that microbes make and in
particular the single molecules, the chemicals that they produce. And what I want to try
and convince you of, in the next few minutes, is that actually microbes
are better chemists than anything we have
ever created as humans. Some of those products they make are remarkably important for us. Some of them are remarkably
disastrous for us and perhaps in the future, some of them will be the solution to some of the biggest
problems that we face today. But I'm going to start this lecture with a topic that is close to my heart and I suspect many of your
hearts, which is that of food. Because food at its first essence is, of course, just chemistry, some really interesting chemistry. And it's probably no surprise
to all of you listening that microbes are a really important part of producing human food. In fact, we consume them every day, whether we like it or not,
in many of the foods we have, sometimes that's not so good
when they cause food poisoning. But what I want to talk about today is how they do some of the
really beneficial chemistry that is so important for human diets. And at its heart, food for all organisms
is all about energy. The unifying feature of
anything that is alive is that it needs energy to survive, to do the things it needs to
do, to replicate, to move, to do all the interesting behaviors that we associate with
microbes and large organisms. And that energy production is central to the existence of all cells. And so I'm going to start with
a little bit of real chemistry, some chemical equations,
I hope not too terrifying. For those of you who are not chemists, I'm hoping you'll still get it, those of you who are chemists, I apologize already that this
is very dumbed down chemistry, but hopefully it will
make sense to everyone. So energy, in all its forms, comes from the food we consume and that food can be a
whole variety of things. And for us, it's genuine food, it's the things we eat,
breakfast, sandwiches, whatever. If you're a plant, it's
ultimately sunlight, it's photosynthesis that drives energy. If you are one of the
chemolithotrophic microbes that eats rocks, it's the chemical substance
in the rock itself that you are using for your energy. But regardless of the
original source of energy, what all organisms do is convert it into something that can
be used in their cells. And quite interestingly, that something is essentially the same for pretty much all living organisms. So if you are a human, or
another animal actually, your food that you take in is something that has energetic value that you can break down. And so as my example today,
I'm going to take sugar, and in fact, I'm being
very economical today, I have only a single prop, but I'm going to use it lots of time. So here is my bag of sugar, I'm
going to plop that on there. And sugar or higher energetic
forms, so carbohydrates, bread, whatever it is, contains carbon, hydrogen, and oxygen. And I'm going to do a
little bit of chemistry here on this hastily assembled whiteboard. So, at it's heart, sugar is
essentially three sorts of atom. It's carbon, it's
hydrogen, and it's oxygen. And I was going to say
you have to remember that, you don't have to remember it 'cause I've just written it here. And so if you take sugar like this, this is sucrose, obviously,
that you put in your tea. This is actually what's
called disaccharide, it has two sugar molecules stuck together. Here for simplicity, I'm
showing only one of those, and very loosely it's drawn as a hexagon because a single monosaccharide sugar, a single sugar unit contains six carbons. Six of those carbon
atoms I mentioned there. So you can imagine your
carbons in the six corners of this sugar, that's a
gross oversimplification, but I'm hoping you're
going to go with me on it. So if you're a human, you consume sugar or some form like it. And then to turn that into useful energy, you have a critical second
component that we all need, which is oxygen. And essentially what we're
doing in our cells all the time is burning the food we eat,
not like you do in a fireplace, but in a very similar
sort of chemical reaction. You are reacting that
input energy with oxygen to produce waste products and energy. And the kind of energy you create or you produce from that
food is a molecule called ATP or adenosine triphosphate. And the really interesting
thing about this molecule is this is what is referred to as the universal energy currency. And you can think about
this in the same way that you think about finance. So all of us have need of finance, you might earn a salary,
you might have a pension, you might have the bank of mum and dad, you might have a pot of gold coins that you discovered at the
bottom of your garden. Lucky you. But whatever form you have,
you receive your money in, it is worthless at that point. It only becomes worth
something when you convert it to a universal currency that
other people understand. So that might be the pound or the dollar, it might be coins, whatever it is. It is something that you
can take to a shop or a bank or wherever and the person receiving it understands the same value from it. ATP is the cellular equivalent. It doesn't matter whether
you eat beef burgers, you have photosynthesize,
you break down rocks, you convert the energy
into this single currency, and now that currency can be used by essentially almost any
biological process in any cell. So this is really important. That process of breaking
down whatever we've eaten to ATP generates a waste product, just like when you burn stuff in a fire, you generate a waste product in smoke. And the waste product, in this case, is water and carbon dioxide. And I think you can see here
where the chemistry comes in because what is the
chemical form for water? Can I pick on somebody? You sat at the front,
I'm going to pick on you. Do you know the chemical form for water? - H2O.
- H2O, very good. Okay, so water is H2O. So you can immediately see, I hope, that your waste products here
contain carbon and oxygen, so you've got these two here, and water, which is these two here. So you've used up all of your
input into these things here. The other thing you've done is you've taken these six carbon molecule and you've broken it down essentially into single carbon
molecules, the C of CO2. So you've burnt your sugar into CO2. Right, that's all the
really hard chemistry done, so you can leave now if
you're a big chemistry nut, and if you're not, you can
breathe a sigh of relief, because the reason for
dwelling on this purpose is that it leads to some
very interesting predictions when you look at other microbes. Because we and many other
organisms are strict aerobes, we can only survive, we can only do this process
in the presence of oxygen. In fact, if I was to deprive oxygen from all of you in this room now, the consequences would be quite swift and pretty irreversible. And we all know what they would be because we cannot live without oxygen, and many organisms are
like that, but not all. There are lots of organisms, particularly some microbes
that don't need oxygen, at least not all the time. And that raises the interesting question about what they then do to convert whatever form of
energy they take in into ATP. So what do you do when you
haven't got oxygen around? And it turns out, there's some very interesting
chemistry you can do there, and it's chemistry that's
really relevant to us. So what you're still aiming to do is create this universal ATP, but you haven't got oxygen. Just like when you're
trying to burn a fire with a relatively limited amount of air, those of you who have a fire at home, you know that if you kind
of shut down the air source, the fire gets dimmer
and dimmer and dimmer. And if you remove all oxygen, if you put a lid on your candle, it'll go out 'cause there's no oxygen. In this case, if there's no
oxygen just like that fire burning in the absence of very much air, you produce less energy. So you do produce ATP but less. So some microbes in the absence of oxygen can switch to this pathway. This would not work for humans, we're too energy dependent
because we need a lot of this. But if you're a microbe,
some sorts of microbe, you can get away with less ATP. And I can give an example- - [Audience Member] What
does ATP stand for, please? - Sorry? (audience member speaks indistinctly) - Sorry, adenosine triphosphate. There's no test at the end though. Yes, the question was
what does it stand for? ATP is adenosine triphosphate, which I'm not going to draw up 'cause it's a complicated molecule. So this process in humans of
converting energy into ATP is happening all the time and it's happening actually at a rate that is quite extraordinary. So in the time I've been talking, which is about 10 minutes according to that clock in the back, each of you in this room
have probably produced about half a kilogram of ATP in your body. So it's about half this bag
of sugar I showed earlier, and you've burnt almost all of that in other processes straight away. You're permanently creating
ATP and destroying it to power all the things that you're doing like hopefully listening to me or perhaps checking your phones or whatever else you're doing, and that process happens all the time. So the average human
being creates and destroys their own body weight in ATP every day. So we can't survive with a
process that's inefficient at producing ATP like this one because we wouldn't make enough. But if you're a microbe and
you have the opportunity, for example, to grow very
slowly or go dormant, you can get by using a process like this that doesn't create as much
ATP, an anaerobic process, one that occurs in the absence of oxygen. But there's an interesting byproduct here because I said in the previous slide that what we do is we break
down all those carbons in that sugar molecule essentially to single carbon atoms in CO2. So we're taking six carbons
and we're turning them into individual carbon dioxide molecules. You can't do that if you
haven't got oxygen to spend 'cause you haven't got
enough oxygen around to break this down completely into CO2. So you have to produce some other kind of waste product instead, a fermentative product, and this is where it
becomes interesting for us because many of those microbes
produce fermentation products that are actually really useful chemicals. Well, useful is perhaps
an interesting question because one of them, of course, is that a product that is very close to our hearts as humans, which
is the product of ethanol. So if you are an organism
like yeast, for example, you can take your sugar source
in the absence of oxygen, you can produce ATP, and you can't fully break down
to individual CO2 molecules. You make a few CO2 molecules, but you haven't got enough oxygen to turn all of this into only CO2, you're left with some carbons. And so you are left with a molecule that has more carbons in it than CO2, and in this case, it's ethanol, alcohol
which has two carbons. That fermentation process
helps your yeast grow in the absence of oxygen
but is very useful for us particularly in the
production of those foods that I mentioned early on, because this guy, this is
saccharomyces cerevisiae, the brewer's or baking yeast, is really good at doing
this fermentation process. It grows very happily in
the presence of oxygen, but if you withdraw
oxygen it can still grow and it produces this fermentation product of ethanol and CO2. And both of those products actually have turned out to be
really useful for humans because, for example, if you put this organism with
things like hops and grains and so on and so forth, you can make it ferment
them into beer or wine or whatever else. The alcohol enters the drink, which is of course part of the point, and the CO2 bubbles through
it to give it the froth, which many of us enjoy. If you put it with other grains
and in a drier environment, it will start to grow fermentatively, it produces ethanol and CO2. The CO2 bubbles up in
your dough to level it, to make it light, and then, of course, you
put your dough in the oven, you burn off the alcohol, which is why we don't get all
drunk when we have a sandwich. But nonetheless, the product, this light fluffy bread is
produced by fermentation. So this process done by a
fungus is critically important for much of the food industry. Not all organisms that can grow in oxygen, they produce ethanol as they're byproduct, there are other interesting byproducts. And this organism here,
this is lactobacillus, it's a bacterium, can
also do fermentation. Just like saccharomyces,
the fungus I mentioned, it doesn't have to, it can grow in the presence
of oxygen, no problem. But if you withdraw oxygen,
it continues to grow, again, once again harnessing sugar, producing less ATP than it
did when oxygen was around, but still a reasonable amount. But it's left with a waste product. It's waste product is not ethanol but this molecule, lactic acid. And you see, again, what's happened here is the original six carbons
have been broken down partly but not completely, there are still three
left in this molecule here because it hasn't been
able to fully burn it 'cause there's not enough oxygen around. But that waste product from lactobacillus is terrifically useful for us 'cause this production of
lactic acid is what sours milk and turns milk into many of the products that many of us enjoy. Yogurt, for example, some of the bacterially fermented cheeses, caffe and other drinks like that. This is a very important process and probably one that was
discovered actually very early during the kind of first
agricultural revolution of humanity thousands of years ago. So in these processes what
we are doing as humans is harnessing some very
fundamental energy chemistry of microbes for our own benefit. But I think, if it stops here, this might be a pretty unexciting story and probably a very unexciting lecture. But I think there's a lot
more interesting chemistry to explore with microbes and I want to take you
through some of that in the next part of the lecture. And actually some of the
most interesting chemistry for microbes comes not from
their interactions with us but from their interactions
with other microbes. And that's because I
think like typical humans, we have a very human-centric
view of the world. We tend to think of
the world as, you know, largely human with some
other annoying creatures scattered through. But
that's not what it's like. In reality, this is a
completely microbial world which is occasionally contaminated
with big stuff like us. But the vast majority of
organisms in this world are microbes, and in many cases, they are living cheek by
jaw incredibly densely in habitats which just
promote competition. And one of those you can see very easily, you can stroll out into
your garden or park, you can dig up a handful of
soil and you'll be witness to one of the most incredibly
densely populated areas on the planet. The average gram of soil, depending on whether it's wet or dry or has a lot of nutrition or not, has between about a million
and a billion bacteria. It has about a million to
a billion fungal cells, and it has probably 10 times
that number of viral particles. So when you hold that
gram of soil in your hand and just for, you know, for estimate a teaspoon
is about five grams. So we're talking about a
fifth of a teaspoon of soil has within it a number of microbes that is somewhere between the
human population of London and the human population of the world. All living in that one gram
of soil very intensely, often competing for the
same kind of nutrients. And so what we all know is that when you have a crowded habitat, organisms tend to compete
and sometimes they do so in a really quite unpleasant ways. And so many of these microbes
have evolved mechanisms to fight off their
competitors within the soil through chemical warfare essentially. And that process has turned out to be incredibly important for humanity. So you can see the process
here in this video. So this is one sort of
bacteria, this is bacillus, commonly found sort of
bacteria also in soil. Over here in this one,
this is streptomyces, these are a group of bacteria, large group of bacteria found
in soils and other habitats that are particularly good
at this chemical warfare, and I'll talk more about that in a second. But this group is kind
of the record breaker in terms of really, really
fancy microbial chemistry. And what you will see here
is that as these two bacteria start to get close to each other, this guy starts to provoke
or invoke its armory and attack this guy over here, and you will see slowly but surely it starts to kill the
bacillus on this side because it is releasing
essentially chemical weapons directed against other bacteria in order to secure its
position in the environment. This becomes interesting
because, of course, chemicals that kill bacteria
or indeed other microbes are pretty important for humans 'cause quite often we want to
kill bacteria in your kitchen, in your liver, wherever they might happen to
be where you don't want them. These chemicals are often what are either in themselves antibiotics or
can be turned into antibiotics. And these, of course, were at the heart of the early discovery of antibiotics. I'm sure you'll know,
this is Alexander Fleming, discoverer of penicillin, and
this is not his photograph, but a photograph of penicillium, the fungus that he discovered contaminating one of his bacterial plates. And he made the very astute observation that where the fungus
grew, the bacteria did not, and therefore surmised correctly that the fungus was releasing
some kind of chemical that killed bacteria that what
now know to be penicillin. A very early discovery of
this kind of chemical warfare. So in the ensuing almost 100 years since Fleming's discovery, we have gone out and we
have looked in environments, not just soils, marine environments, all sorts of interesting places, for other microbes that kill microbes in the hope of discovering chemicals that we can turn into antibiotics, and it has been very successful. People often talk about
this crisis in antibiotics and it's undoubtedly true that we are short of
antibiotics at the moment. But I think it's also worth
stepping back and thinking, in less than a hundred years, how many of these compounds
we have discovered and how many millions
of lives have been saved through the discovery of these kind of chemical
warfare components. The point I want to make
here in this lecture though is that the chemistry of
these is often overlooked, but it's absolutely astounding, and let me give you two examples. So here's one that I suspect
many of you in this room and listening online will have used, this is chloramphenicol. So it's an antibiotic that
you are often prescribed, for example, for eye infections you get, as eyedrop or for superficial
infections, you drop it on, and it's very effective against
many bacterial infections. This is a relatively
simple bit of chemistry. So again, using the same
diagrams we had earlier, there's some carbons in here,
nice little carbon ring, but a nitrogen, some chlorines. Not hugely complicated, although
I mean I think, you know, you can underestimate this. If you were a kind of final
year chemistry student, you popped into the lab one weekend and told your supervisor
on Monday morning, you'd knocked up chloramphenicol, I think they'd be pretty
impressed actually because this is not trivial chemistry, but nonetheless a relatively simple but very effective antibiotic molecule. But now compare it to
some other antibiotics and in particular one called daptomycin, which is used these days
for systemic infections, say for serious
life-threatening infections. Daptomycin is one of those antibiotics produced by the streptomyces, that group I just showed you who were killing the other bacillus. And streptomyces produces daptomycin. And when you look at daptomycin, I think you can breathe a sigh of relief at not having to do this
chemistry artificially because this is what
daptomycin looks like. It is an enormously elaborate molecule, lots of cyclic structures
and ring structures and interesting bond dimensions in there. A really, really hugely
complicated piece of chemistry that's done by a single
celled organism in the soil. And in fact, if anyone was thinking, "Oh, this is actually
not that complicated," the artificial synthesis
of daptomycin is possible, and I'll give you a quick
summary on the next two slides about how you do it. So you start here with
a bit of an extension of the various peptide
length, you recirculize them, here you cross branch them,
you extend, nevermind, and there's a whole second page this. There is a lot of chemistry
involved in producing daptomycin and this would require
large teams of chemists, large industrial fabrication
facilities to do it. And yet a single celled
organism growing in the soil does it all the time
without thinking about it. So I think this is a great example of how microbial chemistry
is incredibly powerful, really quite elaborate and
actually massively beneficial if we can harness it for our own good. So that's a positive story. But I wouldn't like you to go away thinking that all microbial chemistry is marvelous for humans 'cause, of course, quite a lot
of it is not so beneficial. And in particular, sometimes microbes direct
their efforts at competition, not at other microbes but at ourselves. And I think, you know, one
of the key examples of that is in the production of toxins. Lots of microbes produce toxins. I think it's really important, before talking more about these, to realize that they're not doing this just to be deliberately antagonistic. I don't think there are
bacteria out there that think, you know, my aim in life
is to eradicate humanity. They're doing this for one of two reasons. Either they're doing it because the molecule they're producing is directed at something
else, for example, a soil predator that
they're trying to kill and it just happens to work on humans, or they're doing it because
its symptoms in humans are beneficial. And you can think about that, for example, if you are an intestinal pathogen that is transmitted through what we usually call the
oral fecal root very nicely. In other words, you know, people not washing their hands well after they go to the toilet. If you're that kind of bacterial pathogen, it's in your interest to get people to go to the toilet an awful lot. So it's not a surprise
that intestinal bacteria often create diarrhea
and they sometimes do so by the production of toxins. But they're not doing it just
to make your life miserable, they're doing it because
it aids their spread and their persistence. So, you know, the next time
you're stuck on the toilet thinking, "Gosh, I wish I
hadn't eaten that yesterday," have a little bit of sympathy
for the poor bacteria, it's trying to spread
itself as you do that. So these toxins that are
produced by all sorts of microbes are also in their own right some really interesting examples
of fascinating chemistry. And I'm going to start with
perhaps the most infamous, the infamous toxins out there. So this organism is clostridium botulinum, it's a bacteria growing here on a plate. And unlike many of the other organisms we've talked about before, this organism is an obligate anaerobic. It cannot grow in the presence of oxygen. So most of us don't encounter this, it's out in the environment all the time, but we don't really encounter it because we are obligate aerobes, we don't go to places
where there's no oxygen. And therefore, when we're encountering it, for example in the soil, it's dormant, it looks like this and it
produces these little spores that you can see here,
that are not not growing, they're not dead, but they're like seeds, they're immobile in the soil, and they're not harmful
in their own right. And in that state there's no
problem with this bacteria. However, humans are very smart and we have invented lots
of interesting processes. And one of the great
discoveries of, I guess, 100, 150 years ago was
preservation of food. And what we realized is that
if you deprive food of oxygen, it often lasts longer
because many of the microbes that spoil food, that rot
your apples, or whatever else, require oxygen. So many people came up
with this clever idea that if you could keep your food in a way that there's no oxygen
there, it will last longer. For example, if you put it into jars or you put it into cans, like this lady in the 1920s is doing here, that's a very good way of preserving food. And they're right, it's a really good way of preserving food. Unfortunately, if you have not taken steps to remove this widespread
bacteria from those conditions, however, now you've presented clostridium with the perfect conditions to grow in and it will happily do
that inside your tin. And those of you who are
perhaps old enough to remember when we didn't have such
stringent controls on things might remember being warned,
never eat a tin that's bulging, that's still very good advice by the way. If you get a can that is
bulging, just don't go there, because one of the reasons it's bulging might be because this bacteria
that doesn't like oxygen is growing inside that tin. When that bacteria grows, it produces a range of seven toxins that together are called botulinum toxins. Each of them are very, very elegant, and this is a beautiful
example of one of them. This is a protein-based toxin
and what you're seeing here is a kind of skeletal
diagram of the protein. The structure doesn't matter other than I think it
looks quite beautiful. And this is the most potent toxin, still the most potent
toxin that we know of. So botulinum toxins A and B
are the primary ones in humans, and those toxins are so
astronomically toxic, it's quite amazing. So in fact the toxicity of these, the lethal dose is about two nanograms per kilogram of body weight. So that's two billionths of a gram per kilogram of your body weight. So if you are like me, and you know just about the
right side of a hundred kilos, that's a really small amount. In fact, I shall use my same
prop to demonstrate how small. So if I dip my finger in
here and get, I don't know, like three sugar crystals on here, if this was botulinum toxin, this would be more than enough to kill all of us in the room. And in fact this bag of sugar here, if this was not sugar but a one
kilo bag of botulinum toxin, I would have in my hand
more than enough poison to eradicate humanity worldwide easily. This is an incredibly potent toxin, one of the most dangerous
toxins we know of, and yet it still has
some beneficial purpose 'cause it is this toxin, that if you are worried
about your wrinkles, you can get injected in very,
very low dose into your face to improve or reduce your wrinkles. And the reason for that is this
is a very potent neurotoxin. The way it works is you have, obviously, in your body a nervous
system composed of nerves. And if you imagine a nerve
as being long and stringy, those of you who might
remember this from school, you know your typical
nerve has a long axon and these kind of finger-like dendrites. And if you imagine, for example, the nerves that go down my leg, they're end to end like this. So my brain sends a
command to my leg to move and what happens is the
nerve sends an impulse down, when it reaches the end of one nerve cell, it releases a neurotransmitter that crosses to the start
of the next nerve cell and continues that signal
down and so on and so forth. So for my brain to tell my foot to move, there's a whole series of
these end-to-end communications that happen. To cross that junction, they release what's
called a neurotransmitter. So a molecule is released from this nerve, it crosses the gap and
tells the next nerve, time to move the signal on. What this toxin does is
it prevents the release of that neurotransmitter. So although my brain tells
my leg it's time to move now, the nerve takes the signal down but it cannot release that
signal to the next nerve and you end up with what's
called flacid paralysis. In other words, you're totally paralyzed and that's why you die because all the nerves in your body fail to communicate this. But used very, very accurately under careful medical
guidance in a very low dose, what you can do is use the same trick to paralyze individual
nerves in your face. And for those of you who are
like me reaching a certain age where you look in the mirror and think, "Gosh, there's more texture in that face than there used to be," that texture is because I've
got muscles that are kind of, you know, I like to think
they're smiling all the time, but there are lots of
muscles clenching in my face all the time creating those wrinkles. If you paralyze them, your
skin drops out smoothly, and you look years younger allegedly, I haven't tried it, and
it works very effectively. Of course, if you overdose,
that's pretty disastrous. But if you use very, very cautiously, even a really potent toxin like this can have strong benefits. It's by far and away not
the only microbial toxin. There are lots and lots of
really interesting toxins produced by all sorts of microbes. So this obviously is the
fruiting body of a microbe, this is the death cap mushroom. But, as you know already, all mushrooms and toes stools have these microscopic underground
mycelia that are growing, whereas actually the bulk of the organism, this is just the fruit
that comes at the top. The death cap mushroom is
one of the leading causes of poisoning by mushrooms
'cause it looks superficially like many of the mushrooms that we eat. But inside this fruiting body is produced a rather elegant
chemical here, alpha amanitin. Again, you see this really
quite elaborate chemistry here and this is an extremely potent toxin. This particular one works by
blocking a very early step when you want to produce proteins. So when you want to, for
example, express from your DNA a protein that you're going
to need for something, cell division for example,
this toxin blocks that process. And so it is very lethal because
you essentially shut down your cellular protein production
machinery very early on. Much less elegant to look at, but actually even more
insidious, this little chap here, the black dots, this is
ergot claviceps purpurea, this is also a fungus, not quite
as spectacular as this one, that grows on some grain crops. And this has been historically
a big cause of food problems for humanity because this
fungus produces a toxin called ergotamine, which looks like this. And this is a toxin that, again, is affecting your nervous system. It causes severe paralysis
of the nervous system and it leads to what used to
be thought of as a disease that was called St.
Anthony's fire actually, because one of the very
unpleasant symptoms of a ergotamine poisoning is
a appalling burning sensation all over your body as your nerves essentially go into overdrive and tell you that very
bad things are happening. Both of these toxins, highly specific, really very detailed molecularly and a really smart bit of
chemistry done by a microbe. These toxins are relatively blunt tools in the sense that if you give
someone a botulinum toxin, you know, there's a one way to get and it's not going to get better. But one of the really interesting things about some microbe your
toxins is their precision or their combination. Not all toxins are always
toxic, for example. And this is one of my favorite examples, it's recently changed its name, this is coprinopsis atramentaria, I think, which is an ink cap fungus, and you can see why it's called ink cap 'cause it has this kind
of black sticky surface. This guy produces another
toxin, coprine, up here, a fairly simple molecule actually, and on its own, this is not toxic at all. You can go out and eat these,
I wouldn't recommend it, but you can, and you'll be perfectly safe. Unless you choose to
eat these in conjunction with an nice glass of wine or a beer because this is a very neat chemical. It is not in itself toxic, but it is a very potent blocker inhibitor of acetaldehyde dehydrogenase, which is the enzyme that you need to detoxify the poisonous products that are created by ethanol in your body. So if you drink on its own, you're fine. If you eat this on its own, you're fine. If you put the two together, this molecule stops you
being able to detoxify this and what was previously
a harmless pint of beer is now potentially a
lethal source of poison. That combinatorial chemistry, if you like, that use of a toxin with some other thing is kind of a common theme in microbiology. And I think one of the
neatest examples of that comes from a bacteria and this bacteria is the green thing here. So this has a beautiful name
vibrio parahaemolyticus, and it is this little green
chap that is responsible, if anyone has suffered this,
for acute shellfish poisoning. So this is the thing that often
people have had, you know, prawns or oysters or something,
and within a few hours, you know that something was not right. You have serious, serious diarrhea and you are in a bit of a miserable way. And that is often because this organism, which lives in marine environments, has set up home instead in your intestine. And what vibrio parahaemolyticus does is it sticks to your intestinal cells, so here are intestinal cells in red. It sticks to them and then
it injects into your cells a series of proteins that it needs to do what it needs to do to replicate. But unfortunately, which then
leads to quite a lot of damage and death of your intestinal cells, which is why you get this, you know, horrendous diarrhea as
your intestinal layer is stripped off essentially. To do that, like any kind of good doctor, vibrio needs a syringe
to inject things with and it creates a syringe, which
you can just about see here. This is an electron microscope
image of the syringes, they're called type
three secretion system. And it looks a little bit like a syringe, I think, you can agree, it
looks like the kind of thing, a needle that you might want
to inject something with. These are very complicated
molecular machines that assemble on the surfaces of bacteria and then inject proteins into human cells. A really neat piece of biology, but actually a really expensive
piece of biology to create, if you are a bacteria. It takes a lot of energy
and a lot of production to make one of these things. So you don't actually want
to do that all the time. If you are sat in your prawn
out in the North Atlantic and you don't need to do this at all, you don't want to be wasting
energy producing a needle you're never going to need. And so to avoid that waste,
what vibrio has done, has combined this very
elaborate toxin system with a really neat trigger. And the trigger is a molecule
here, another protein, VNTR, which sits on the surface of the bacteria and it's a sensor and it's
looking for something. And what it's looking for is
a tiny little green molecule that you see here. This is a bile salt, a human bile salt. And these are the things that
you produce in your intestine to help with digestion essentially. Those of you who like William Shakespeare will remember all these crates about bile as in the kind of the
black nasty noxious stuff in your intestine. But bile salts are a really important part of helping us to digest our food. What vibrio has done here is it's realized that bile salts are not
present out in the environment, they are present in intestines. So if you wait until you see a bile salt, then you know you're in the right place to produce this really expensive machine and generate all those toxins. So it doesn't do any of this until it senses a bile
salt in the first place. A very neat bit of trickery. And this I think is also kind
of an interesting opportunity for us medically because essentially what we're saying is that until it senses a bile salt, this bacteria is harmless,
it's not producing a toxin. So if we could, for example, develop a way to trick
it into not realizing that it's in the human intestine, you might be able to eat
even contaminated shellfish without any problem at all
because they go straight through without producing the
toxin in the first place. I think that's a long way off, but an interesting example of how learning a bit of chemistry might help us deal with
kind of real world problem. So we've talked a bit about toxins, we've talked about some of
the beneficial molecules, like antibiotics that microbes produce. For the last few minutes what I want to do is turn our attention
to some of the things that they can create, some of the materials they can create and some of the potential, I think, which is huge for future
chemistry using microbes. And the reason for this
is because microbes, we are only just scratching the surface of the kind of chemistries
that are out there. I mentioned before that, you know, the whole field of antibiotics is only about a hundred years old. In that time we have
discovered tens of molecules, saved millions of lives just
by essentially looking in soil. Today we have all these
amazing techniques. We have mass genomics,
you can take sea water, you can sequence all the DNA in sea water and work out what's there. We can take human intestines, and we can look at the kind
of feces you have in there and realize that there
are literally hundreds and hundreds of species
living in human intestines that we have never previously identified. So I think it's reasonable to assume that if there are hundreds, thousands, probably tens of thousands
of undiscovered species, there are also hundreds, thousands, tens of thousands of undiscovered
chemistries out there, some of which might be useful to humanity. And I've got some
confidence in saying that because we know it's starting to be true. So for example, a few years ago people discovered
some microbial chemistry that has the potential to solve
one of the largest problems of our time that of plastic waste. So this is a typical image that I'm sure all of you
are now familiar with, of, you know, the mass of plastics, both macro plastics like these and micro-plastics the ones
you can't see in seawater, in soils, in pristine environments. And that is because
plastics, by and large, are not biodegradable, and in particular a
big problem one is PET, polyethylene terephthalate, which is the plastic that is used to make disposable water bottles
and those kind of things. It's a really, really useful material but unfortunately doesn't break down and floats and accumulates
in biodiverse systems. So what we need is a
way to get rid of this. And it turns out that some bugs
have already realized this. So this is ideonella, this is a bacteria discovered
just a few years ago actually, which thus far is one of
the very few organisms that seems to have the capacity to break down these kind of plastics. The moment it is very slow, it does do it, which is great, but nowhere near it the
rate that you might need to deal with the world's plastic mountain. But actually just in the last few years people have looked at
ways to grow this organism differently for example. And in doing so, they have discovered ways
that you can accelerate it's breakdown of plastic many times. And so I think it's reasonable to assume that within perhaps a
few years from there, we might have a decent
microbiological solution to this plastic mountain. I mean, I should point out, this is not an excuse to
throw your bottles away because clearly there is still
an issue of how you get this to where you need it
to deal with a plastic. But nonetheless, an opportunity
here provided by a microbe rather than human chemist for dealing with one of
humanity's big pollution problems. This is potentially even
bigger pollution problem, radioactive waste. When it's like this and neatly stored and carefully archived, it's
not so much of a problem. But as we all know, when it leaks it's potentially
a massive disaster. And particularly when it's
dissolved in water courses and can spread even low level radiation can be very, very harmful. And yet just a few years
ago people discovered this rather than any organism,
this is geobacter. And geobacter really likes all sorts of interesting heavy metals including uranium, for example. And what people discovered was that if you put geobacter in soils where there is some uranium, it will use some of the
energy from that uranium and turn it into a uranium salt. And in doing so it precipitates it, makes it insoluble and it
drops out of the water course. So you could add geobacter to
a contaminated area of soil, it wouldn't get rid of
your uranium problem but it would stop it spreading
and moving beyond that area. That was already quite a neat trick, but what has materialized in recent years is something even more exciting I think. So you can see in this image that geobacter produces
these long fibers here. It is those fibers that it uses to capture metals in soils
or in water like uranium. It does that for its own purpose, its own energy gathering purpose. But as it does that, this fiber becomes
electrically conductive. It's like a little copper wire or in this case a uranium wire, and it can do that for
lots of different metals. And in fact, it can turn itself into a
little tiny electrical circuit. And this is something that
people are very excited by because the scale here is absolutely tiny. This thing is producing
electrical circuits at the kind of scale we need for things like transistor
circuits for cell phones, for computers, for satellites. And so maybe there's an opportunity that we could harness
geobacter to create electronics at a scale that we can't currently do using manmade techniques. That process of, if you like, electronic manipulation is interface between biology and technology is an area that's really, really exploding and very exciting. I want to share another example, actually a very recent example, of something that is similar in that vein. So I suspect many of you
will have heard of Graphene. Graphene is this wonder material that won the Nobel Prize some years ago. And essentially one of the
cutest things about this as people might know is that
it was originally discovered through a kind of very sort
of lab-based experiment using cello tape and pencils because graphene is essentially
single layers of graphite, the thing that is in pencil lead. It's not quite that simple though because graphene layers typically oxidize, have a lot of oxygen
groups on the outside, and that means they're not very good at doing all the electronic
things you want them to do. So to make graphene usable by humans, what we do is we take graphene oxide and we have to reduce it, we have to get rid of those oxygen groups. At the moment, we do that using a lot of
really noxious chemicals, you have to treat this
thing in quite toxic, quite unpleasant conditions to
remove some of these oxygens and turn it into this usable form. It works but it's not great. Turns out though, as with
many examples tonight, that bacteria got there an
awfully long time before we did. This little bacteria here is shewanella. It's a marine bacteria, and it turns out that it's
able to do this reaction without any need for any
noxious chemicals at all. And in fact you can see
this very nice graphic from Anne Meyer, who
did some of this work, where essentially you
can mix your bacteria with your graphene oxide, it will do all the heavy chemistry for you and turn out the other
end a very nice graphene, a reduced form of graphene that you can use in your electronics. And you can see in fact here, so this is the graphene
oxide that you can't use, you need to turn it from this orange color to this black color. And you can see that if
you do it either chemically or microbially, there's
actually no difference. And so here is a process
where we can create a very useful man-made material without using these
environmentally damaging chemicals, all by virtue of a bacterium. So my final example before I
close though is the potential, I think the potential here. So far everything I've talked about are, if you like, natural processes, these are things that bacteria and a fungi have evolved in order to be able to deal with problems they have that might also be useful to us. For example, the
production of antibiotics. But what about when you combine the kind of natural
diversity of microbiology with some of the kind of
human potential we have and in particular the potential
for genetic engineering. And one of the things
that a lot of bacteria are very good at is accepting
genes from other organisms and doing stuff with them. They have done this for
millions of years actually. There's nothing new about
genetic engineering, bacteria always picking up bits
of DNA from the environment and doing stuff with them. But humans have learnt to harness that. And so you can produce, in bacteria, all sorts of interesting things that they're not normally going to make. So insulin, for example,
if you're a diabetic, your insulin is probably
coming from a bacteria that is producing that. And one of the nicest examples, I think, is this final one here. So silk, spider silk is a
material, as I'm sure you know, that has huge potential,
enormously strong, really light, biodegradable,
all sorts of benefits. If only we could make this in a way that didn't require spiders, which are tricky to work
with, that would be great. And indeed a group in Japan
has recently done that. They have taken this
organisms rate of volume and they have expressed
in this a spider protein that allows it to produce spider silk. It's not quite as elegant
as the spider silk that you see here, but this is a single
fiber of that spider silk. It's very early days, but that silk looks actually
and feels quite similar to the kind of classical spider silk. But now, of course, you're
producing it in a bacteria and there are two big benefits there. One, this thing is photosynthetic, so you don't need to
feed it lots of energy, you don't need to feed, it flies, you can grow it in sunlight and it will produce for you this silk. Secondly, there is no
limit to the scale here, you can grow bacteria in liter vessels, a hundred liter vessels,
massive factories. You could produce huge
quantities of this silk from those organisms for use in all sorts of
interesting man-made materials. And I think that really is
the point I want to end on with the excitement and the potential of this for the future. And with the proposition
really that maybe in 10, 20 years from now when we
think chemical fabrication, we will be thinking less about large chemical factories like this and more like biological
fermentation places like this, is my proposition, come back in 20 years and
tell me if I was right. Thank you very much. (audience applauding) - Thank you a lot, Professor May. We do have time for a couple of questions. So what I'll do first is I'll take a few from
the online audience and then I'll open it up to the floor. So the first one is a little
bit back to the chemistry at the start. Where does the phosphorus
in ATP come from? - Oh, there's always a
chemist online, isn't it? That's a rule for life. Yeah, so when I said it was
very oversimplified chemistry, that's right, I said phosphorus, in fact, there are far more elements
than just these three that are obviously essential for life. Phosphorus in those cases, so for us, phosphorus
is coming from our food. If you are a photosynthetic plant, you're gathering phosphate from the soil. And those of you who might
have seen my first lecture, we talked a bit about this symbiosis between a fungus and a plant where the fungus is donating phosphate, so phosphorus to the plant to then use. So yeah, you need phosphate,
you need lots of other things, potassium as other example
from other sources, either the soil if you're a plant, rocks if you are a microbe,
or food if you're a human. But thank you for picking me
up on my oversimplification whoever that was online. - Thank you. We do have one about microbes and how they break down plastic. So could you just tell us a bit more on the actual process involved? - Yeah, so it's still
largely unknown actually, the full details of the
kind of chemical process, it looks like... So plastics are actually
very useful feed stock, if you like. I don't do this at home, but if you've burnt plastic in ventili, you know it actually burnt really well. It's a hydrocarbon, it's an oil derived thing
like petrol or diesel, so there's a lot of energy in plastic. And so in some senses it's not surprising that some microbes want
to use their energy so they're breaking down the plastic in the same way that we
break down that sugar or something else for
their own energy use. How they do it and what they
produce at the other end is still a bit vague, and one of the big challenges that we have is making sure that what
they're producing from it is not in itself harmful. So you obviously don't
want to break down plastic into two equally harmful
things that then diffuse away. And so that's kind of
watch this space answer, I think for that. - Do we have any
questions in the audience? My colleagues' just bringing you a mic. - [Audience Member] Sorry. It's just thank you for
very good talk by the way. It's just a follow on from
the plastics piece there. So how do you mitigate against,
as these bugs are developed, which can do a great rate. If they're not used in that context and they're just prevalent
in the environment, surely they can degrade
structural plastics and containers and things which are needed
to do their job right now. So how do you get one
thing without the other? - Yeah, that's a very good question. So in the specific case of Ideonella, so the organism that's this, it's actually not a very
widespread organism, which is why we don't get, you know, you don't go to your supermarket and discover all the
water bottles collapsing because of this. But I think that's a valid concern when we start to think about if
you're going to engineer this, say for example if you're
going to take that ability and put it into a much
more widespread bacteria that might be useful
for all sorts of things, you'd want to be pretty sure that if you're going to release
that to the environment, for example, that it's not about to
destroy the plastic industry and civilization as we know it. But I think in terms of
why we don't see more, I mean that's an interesting question. The straightforward answer, the
plastics are relatively new. Evolutionarily speaking,
they're incredibly new. We've only had plastic
for about a century or so and so there has not been
time for organisms to evolve. You could play that
tape forwards and think, okay, what about a
thousand years from now, actually, will we see that
bacteria have diversified and there's now a whole
bunch of really good bacteria that are a problem because they are feeding off
all these man-made plastics that we've created, which
is a plausible scenario. I guess, I won't be
around in a thousand years to find out whether I'm right or not, but it it is certainly a possibility. - [Audience Member] Bacteria being able to break down plastics. So is it a safe enough assumption to think that we will also be able
to use some microorganisms to break down all the oil
spills that have been happening in the sea and oceans because since plastics
are also natural gas and oil derived products? - Yep, yep, that is a
very safe assumption. And the reason I can say that is that we actually already
know of some organisms that are capable of breaking
down petroleum products like oil slicks and there's been a lot of
interest actually in two areas. So one is in terms of natural
organisms that might be used, for example, in oil spill in
the ocean to degrade the oil. And so geobacter that one I
talked about with the metal also actually has a second ability to degrade some petroleum products. The second aspect of that is it can also sometimes be a problem. So, in oil tankers, you can sometimes get microbial
contamination of the oil and that's actually a real nightmare because it's then growing on the petrol and causing all sorts of problems. So a bit like the answer
around the plastics, there's a kind of ying yang there. I think the key question
for us, really, it will be, how you get that activity in
a way that is controllable to remove where it's a problem but not to inadvertently
remove petrol engines. Although, of course, actually
there may be good reasons to remove petrol engines
for other purposes. - [Audience Member] I was
interested in the geobacter and the comments you're
making about uranium. And I was wondering if there was any work to look at recovery of rare earths and transition metals
from electronic waste? - Yes, there's there's been
a lot of interest in that, how you might use... So one of the things
bacteria really good at is taking stuff that's very, very diffuse and concentrating it because
they want it in their cells. And so one of the most
interesting examples I've seen of that actually
is from catalysts in cars. So all of us, you drive cars, and you have a catalytic converter. There are lots of relatively rare metals in that catalyst that are
helping to break down, you know, the dangerous fumes you are
releasing from your exhaust. Over the lifetime of vehicle, those metals are being
deposited in your exhaust fumes onto roads. So roads have actually a
reasonably economically viable amount of these rare
metals on their surface, but you can't get them because they're spread
across the road network. There's been some really
interesting work using bacteria that are particularly good
at harvesting these metals with the idea that you might
be able to, for example, wash all your bacteria and
then there were some bacteria, for example, that are magnetic and so you
could combine those traits. What about if you could
wash all your bacteria, leave them for a day, and then
come back with your magnets, scoop them all up, and voila, you've got your palladium or, you know, whatever the rare metal is that you want nicely concentrated. I think there's lots of
potential there also for mining. People interested about
whether you could do this in a much less damaging way. Could you mine by putting bacteria in then pulling them back out instead of drilling massive holes. So yes, lots of potential. Pretty early days, but
quite exciting I think. - [Audience Member] So I had a question. You talked about geobactor. So in that you talked about how it can be used as electrolytic cells. How uranium and the
heavy metals can be used as the thread that is in the geobactor acts as a copper wire, et cetera. So these cells, most probably,
won't be rechargeable because since the heavy metals would be converted into the salts. So what if like, you can shed light on how these can be used as viable cells in our normal lives? - Right. That's a very good question. Yes, and very stupid a chemistry. So to deposit the metal you
need to do something with it, like turn it into salt, which might in itself make it less use. At the moment, the way people
are thinking about these, I think is not as a
living electronic circuit. I don't think people are envisaging, although actually it's
an interesting concept that you'd have your
kind of live bacteria. But what you might do, a little bit akin to the previous answers, you might get them to
synthesize these fibers. You could then harvest the
fibers, a bit like we harvest, you know, silk from cocoons or
something, you know, cotton, and then you could treat it in a way that might remove the salt, for
example, and make it usable. Ultimately, I could imagine
what you could do possibly is tweak the biology of the microbe so it doesn't even do that
annoying bit in the first place. But that's much further down the line. But even now, I mean,
we're used to doing this, a lot of the products that
we use from microbes already, when they're produced by the microbe, but not immediately usable, you have to do something to them. But what you have to do to
them is much less onerous than what you would've had to
do to create them from scratch in the first place. - [Audience Member]
There's an older wives tale from my part of the
world, which it goes that, phosphates are in fish and
if you eat a lot of fish, that's good for the brain. Is there any evidence of that? - I feel like I'm on
thin ice here, advisor. So phosphate absolutely important, you can't live without phosphate,
so that's quite important. How much phosphate you need in your diet and whether you should
eat fish is up for grabs, I would say. I mean, separately from that,
the evidence for oily fish, some oily fish in your
diet being very healthy is pretty strong. But in terms of, for example, microbial based phosphate
to stimulate diets, I mean there's lots of
interest in, as you know, in sort of probiotics for example, in microbes as dietary supplements. It'd be really interesting
to look at that, probably not for phosphate, which we get quite a lot of already, but for some of the trace
elements that you need in diets, lots of interest about
whether you might be able to harness microbes to do that. And I think old wive's tales, I think, you know, or folk legend, if you like, I think, are a really interesting source of kind of questions that
can be answered by science in that context, absolutely. - [Audience Member] I think you
partly answered my question, which was posed by someone else, but I'm going to ask you anyway. Generally, in history,
when we tinker with nature, there are unforeseen consequences, and a lot of the solutions that you've put forward
are solutions to problems because we've tinkered with nature. So plastic isn't our problem until you really put it
on an industrial scale. When we start deploying things that are at a very small
level that you can't see, the risks become huge because
we can't see what's happening. So what's your view on
us tinkering with nature at this very small level and what are the potentially
unforeseen risks in the future? - That is a lovely question. Have we got another couple of hours? So what do I think about, I mean, so you're absolutely right that a lot of the problems
that the world faces today are problems of humanity's creation. In fact, not just plastic, I mean, you could argue that uranium waste is also our own production problem. That not with standing though, we have the problem, we've got to fix it. So I'm kind of a big
believer in doing both. So you absolutely have
to change behaviors. So climate change is a great example. We absolutely have to
reduce carbon emissions, period, full stop. We also need to do
something about the fact we already have far too much CO2 and so we're going to need some
technology solutions there. So I think, so the short answer is I
think I believe in both. I totally take your point. I mean, I think with any
kind of intervention, particularly an intervention which might ultimately
become out of your control. So if you're going to do
something in the wider environment or release to the environment, you want to be as sure
as you possibly can be that you've mitigated all those risks. And I think, you know, in the UK we have a pretty
robust system for that, that's not true of all countries actually. And so there is a big challenge here about kind of international agreements on when you might do
something, when you might not. Climate change is a great example of that, doesn't matter if, you know, half the world reduces emissions, if the other half keeps growing them, we're still in the same problem. So I think that that question
of how you address the dangers and the benefits of playing
with nature is really important. What I would say though, I think is that, that is not a reason to not do it. I think there is a lot
of potential out there, and I think a lot of our
existentially challenging problems that we face can be solved
with these kind of technologies if they're appropriately applied. So I would urge I guess from
my position, go forwards, but go forwards cautiously. - [Audience Member] Curious about silk. When they're all in that
vat, do they produce fibers, or how do you get it to become fibers? - Yeah, so in terms of the silk
production, so the early... I should hate this now,
this is very early days. What's been produced at the
minute are very short fibers. They are fibers but you
can't go rock climbing with one of these silk fibers yet. But I think there's two things there. I mean, one is that you might be able to weave these into much
large, even small fibers. You know, cotton is a small fiber, but you can produce
pretty impressive stuff. But secondly, I think, you know, this is a very early step and that we could end up creating microbes that produce far longer fibers, potentially for use to things like ropes and Kevlar vest and so on and so forth. - Well, thank you all for your questions. Please join us on Wednesday,
the 8th of February, for Professor May's next lecture on Microbial Record Breakers. Thank you again, Professor
May. (audience applauding)
