In Our Time - Enzymes

Episode Date: June 1, 2017

Melvyn Bragg and guests discuss enzymes, the proteins that control the speed of chemical reactions in living organisms. Without enzymes, these reactions would take place too slowly to keep organisms alive: with their actions as catalysts, changes which might otherwise take millions of years can happen hundreds of times a second. Some enzymes break down large molecules into smaller ones, like the ones in human intestines, while others use small molecules to build up larger, complex ones, such as those that make DNA. Enzymes also help keep cell growth under control, by regulating the time for cells to live and their time to die, and provide a way for cells to communicate with each other. With Nigel Richards Professor of Biological Chemistry at Cardiff UniversitySarah Barry Lecturer in Chemical Biology at King's College LondonAnd Jim Naismith Director of the Research Complex at Harwell Bishop Wardlaw Professor of Chemical Biology at the University of St Andrews Professor of Structural Biology at the University of OxfordProducer: Simon Tillotson.

This is the BBC. Thanks for downloading this episode of In Our Time. There's a reading list to go with it on our website, and you can get news about our programs if you follow us on Twitter at BBC In Our Time. I hope you enjoy the programs. Hello, enzymes are essential to life. Their proteins found throughout our bodies and all living organisms, and their role is to increase the speed of chemical reactions.

In our guts, our brains, our lungs, throughout our bodies, they enable reactions up to thousands of times a second. reactions which might otherwise not happen even in the lifetime of the universe. Enzymes were noticed first in yeast, in breadmaking and brewing. The name comes from the Greek in yeast. And for over a century, won the Bell Prize after another has been awarded to scientists who have helped to explain how enzymes are made and how they do what they do.

This has led to breakthroughs in medicine and hopes for a new and cleaner way of doing chemistry in the man-made world. With me to discuss enzymes are Nigel Richards, Professor of Biological Chemistry at Cardiff University Sarah Barry, lecturer in chemical biology at King's College London, and Jim Naismith, Professor at St Andrews and Oxford University's. Nigel Richards, what did scientists see in the 19th century that made them think that something like an enzyme was at work?

Okay, well, you can trace it back, actually, to the beginning of the 19th century, although it really goes back thousands of years. I mean, the fundamental thing that humanity discovered was, as you pointed out, how to make bread, how to make wine, fermentation has obviously been a big part of human history. And this led to the initial idea that change could happen in biological systems. And it could happen quite rapidly.

And things really came to a head, actually, in 1834 or thereabouts, when the French wine industry was undergoing a terrible collapse because the wine was becoming acidic. And so you couldn't store it. And so millions of liters of wine basically looked like it would have to be thrown away, and this was catastrophe. And so it turned out that the wine makers, the brewers, went for help to a man called Louis Pasteur to find out why this was happening.

And Pasteur realized, because he had very good technology, the microscope, that this was happening because of yeast contamination in the wine. And this was interesting because, you know, you need yeast to make wine, you need yeast to make bread. And suddenly, yeast was also involved in this destruction of wine. And so people began interested in why did this happen? What was yeast doing to change the chemistry of wine and to even change the chemistry of sugar, right?

I mean, to get alcohol, you need to add sugar. But alcohol and sugar are very different substances. And if you leave sugar on the shelf, it doesn't usually turn into alcohol. So there was a driving force to understand why these changes were happening and what caused these changes. And there was also the view that there was something special about these changes to do with the fact that living organisms carried them out. Chemistry was in its infancy, was beginning to develop.

but people had not married the two components together. That actually didn't happen until the end of the 19th century when someone had the bright idea of taking yeast, breaking them apart, and seeing if what was inside the yeast could do the chemistry without the living organism. What kind of reactions were being speeded up by these enzymes? Okay, so it was mainly to do. do with sugars, and starches. So if you take starch, you can break it down into glucose. You can do it chemically with acid, but you can do it much, much faster by taking the extracts out of organisms

like yeast, and you get very rapid conversion. And this was a perfect reaction to study with the technology of the time. It can be followed very, very easily, and the rates can be measured, quantitative. And then once you've got that simple technology working, you can then start to fractionate parts. You can take different parts of the yeast extract and try and figure out which part causes that to happen. Clearly, alcohol production was of great interest to winemakers. How did that happen? And people become very interested in trying to isolate the enzymes that were involved in that whole process and to try and begin

to refine what was going on. But you need to understand people didn't know what enzymes were. All they knew was that there was something inside this organism that made the reaction happen faster. Thought for a long time to be magic. Jim Naismith.

So the enzymes became catalysts. Can you tell people what that means in this context and how it worked? So catalysts, just make, as you said yourself in the introduction, make things go faster. And I guess most people will know about the catalytic converters and cars. So enzymes are no more difficult, I think,

to understand in catalytic converters or lots of other things that we see around us, that they make reactions possible that would otherwise be very, very slow. Enzymes are quite, the enzymes do something that's very interesting. Let me give you an example of a catalyst. you and I are both at the top of Buckabrow and Settle.

It's a great big long hill down into the town. If we have to walk down there, it's going to take us a lot of time and energy. If we both sit in a bike, we'll wheel down, and the bike is a catalyst, it's unchanged by the process of going down that hill. But it has made us much faster to do that. And so enzymes work in that way that they make reactions, which are going to be favourable, happen much more quickly by lowering the energy required to do that reaction.

Can you just tell listeners what an enzyme actually is? An enzyme is an assembly of amino acids linked together by peptide bonds. Now, most enzymes are in fact proteins, but that's not how they began. They began as nucleic acids. So we still see, interestingly, for those that study them, we'll see elements of nucleic acids embedded inside enzymes. So that sort of ancient history is living fossils inside enzymes today. The ribosome that makes proteins is made of RNA,

So we can see enzymes of protein, of RNA that still exist today. What would have happened if enzymes hadn't turned up? There would be no life. There is no life without enzymes. Life is a constant fight against disorder. You need to be able to stick things together that want to fall apart. How do they stick things together? They make bonds that are normally life works by sort of kinetic traps.

So if you think of my glass of water on the table, that's thermodynamically speaking unstable. It would like to be on the floor. Why? Because it's lower in energy. Water flows downhill. But it's trapped inside my cup. So to get it on the floor,

I have to supply some energy to get it over a barrier. Now, enzymes do funny tricks. So let's, if I extend that glass of water analogy a little bit, if you're in a 104 building and I'm in a 90-floor building and we're a part by a plaza, for you to get that water to me in 90, 10 floors down, it's energetically favourable.

But you'd have to take it all the way down, walk across the plaza and come up. Enzymes supply a drain pipe from one building to another. The water flows down the drain pipe. The drain pipe is unchanged, but the water has lowered its energy. And they can move at colossal speeds, can't they? Yes. I mean, you're talking a million exchanges a second now? Yes, so one way to think of it is enzymes can accelerate rates by 10 to the 17.

That means 10 with 17 zeros after it. So the lifetime of the universe is about 10 to the 16. So a reaction that might take the whole universe can be done by an enzyme in less than a second. I think I'll take a deep breath at this point really. When you get it and I say, so are we talking about biology doing chemistry in a way, aren't we? Yes, I mean... So what's different about biology and chemistry? Well, I'd like to say there isn't anything.

That's one of my pet things is that chemistry is really biology or biochemistry is just chemistry. You're getting heavy nods from across the table. That question was badly phrased by me. Thank you for putting it right. No, you're absolutely right. This is a thing that's because at school, we teach chemistry as a subject that it was 100 years ago. We don't teach chemistry as it is today,

which is a big expansive subject. Sarah, can you give us some idea of the range of chemical reactions in living in organisms, such as the human body, that enzymes speed up? Can you give us some examples of the way operates? He's operating now in each one of us and those at the other end. So the important enzyme, there are many, many families of enzymes that catalyze a whole range of chemistry. And we define, we put enzymes in brackets, we put them in these families, largely dependent on what kind of chemical bond they make or break.

So we can divide them into classes, if you like. So, for example, proteases are involved in breaking down proteins. so you'll find them in your digestive system. So every time you eat some meat, meat is made of protein. There has to be broken down in order for you to use the components of that meat in any biochemical processes in yourself.

So they'll break down a chunk of meat. Very quickly. What's relatively? I'm not sure how fast proteases work. But fast enough for it to, you know, if you think about how fast your digestive system works. So if you'd have to meet on a bit of table, it would take it years to become what it'd become in your stomach in a minute. Exactly.

Well, maybe not that quick. But so that's an example of an enzyme that breaks bonds. So a bond that is very stable. The peptide bond, as Jim mentioned already, is a very stable bond. So if you leave a, if we wanted to break it down chemically, so to compare it to the chemical reaction, we'd have to use very harsh conditions. We would have to heat it up.

We would have to provide a lot of energy to the system. And what enzymes allow you to do is to do that same reaction in a human body at 37 degrees quick enough so that you can access the small building blocks that you need to do other reactions in your body.

In the sense, are they driving evolution? They themselves are revolved part of evolution. So an enzymes... They're part of it, I'm driving it. They're creating DNA, but DNA is part of them as well, isn't it? Yes, yeah, yeah, exactly.

So enzymes are involved in DNA replication. So you've got a massive enzyme complex involved and actually forming the bonds between each of the bases in the DNA molecule, so polymerizing the DNA. And that is another kind. So that's an example of a set of enzymes that are involved in making bonds rather than breaking them. Is there any way of telling us what an enzyme looks like? It's a good question.

Enzymes, in terms of shape, I can possibly pass you over to Jim in a moment because he is an expert in this area. But they adopt a whole wide variety of different shapes. So it's not necessarily that they have a defined, any one defined shape or that it's necessarily easy to predict what shape they're going to adopt. So they start off, all enzymes are, well, most enzymes are proteins. And they'll start off in if they're proteins as an amino acid sequence, a linear sequence. And that has to fold in the right way for it to adopt a specific shape. And within that, you'll often, specifically for enzymes, you have to have some space for the chemistry to occur, some gaps in what we call an active site.

and that's where it will bind the molecule that it's going to act upon. But certainly Jim can maybe mention a little bit more about how we structure or how we determine the structure of enzymes. Yeah, I mean, as Sarah said, the assembling to shapes, another way to think of it is if I go back to my bike analogy, bike is just a bunch of components. It does nothing unless it's precisely assembled into the correct shape. So an enzyme has a three-dimensional shape that fits its function.

and we do that by a technique called protein crystallography so we fire x-rays at crystals or we can also use NMR or increasingly electron microscopy. And that was something the UK pioneered really was the structure of enzymes. So Bernal in the 1930s showed that crystals that have been growing of digestive enzymes behaved like salt crystals, the diffracted x-rays. And then we went through Max Perutz and David Phillips and Dorothy Hodgkin. And it's always think it's a show.

shame that we know less about Dorothy Hodgkin maybe than Rosalind Franklin, but Dorothy Crowfoot Hodgkin was a chemist who did the structure of insulin and vitamin B12 and won the Nobel Prize in chemistry. She's a unique figure in British scientific history. And, you know, not enough kids see her. I think she's an inspirational figure. Can I come back to you, Nigel, Nigel Richards. What properties do enzymes have that allow them to enable so many reactions so quickly?

Okay. So the fundamental problem about doing a chemical reaction is you have to put the electrons, the glue that hold the atoms together in molecules. You have to arrange them very precisely in three-dimensional space before a reaction can happen. So most reactions are slow because the molecules bang into each other randomly

and the electrons cannot change their bonding. They cannot change the kind of chemical bonds they're involved in because of these random processes. And so for anything to happen, it has to be slow because one time in some huge number of collisions, you'll have the correct three-dimensional arrangement of electrons and the reaction can happen. What an enzyme does is it does two things,

is it takes the molecules, the chemicals that are going to undergo the reaction, and it orientes them very precisely. So the electrons are in exactly the correct locations in space to allow the chemical bonds to be formed and to break. The second thing it does is because of the properties, because of its charge properties, its shape properties, it creates very large, what are called very large electric fields, and these electric fields can be used to manipulate the chemical bonds

to make them weaker than they normally would be if the molecules were just floating around in water or just doing what they can. So you get two effects. You make the electrons more willing to react by putting them into this very carefully designed environment. And by orienting the pieces of the molecules correctly, every collision gives rise to the chemical reaction.

And so the two things combined allow you to do chemistry at much faster rates than would normally be possible if the molecules were just moving randomly in space. As you're talking, I'm thinking of this intense activity of going on inside all of us. I mean, your notes who said that we are just a pool of chemicals? Well, probably not me, but it's...

You quoted someone saying, as distinct from Hamlet's saying, what a piece of work is man, we've got, we are just a pool of chemicals. Oh, right. So, yeah, yeah, I mean, there's the number of chemical reactions that are going on in your body right now.

I probably in the millions. In every single cell. Remember, every single cell is doing chemistry. You have different kinds of cells in your body which have to do different kinds of chemistry to carry out their function. Your liver, my God, your liver. Liver cells are responsible for essentially processing out

all of the toxins that accumulate in your body. And the chemistry done by a liver cell is fantastically complicated compared to the chemistry done by, say, a lung cell or a brain cell even. Although the chemistry in the brain is very, very complicated, and you need special enzymes to manipulate the molecules in the brain. How many enzymes are there? I'm going to, if anybody counted. Well, so people have estimates, I guess.

It's at least 10,000, and it may be 100,000. It's a huge number of different possible reactions. And like I say, as Sarah said, we group them into categories so that we can organise all of this chemical information in an accessible form. Is it possible, Jim Naismith, to talk about, to me very specific,

how does the absence of one enzyme make a difference to what an organism can do? Okay, so we can think of that in a couple of ways, and let me start with the one that maybe some of the listeners may know in white European stock, most of us can drink milk in adulthood. That's because we persist to produce the enzyme lactase that breaks apart lactose, which is in milk. But that's not common in populations from China and parts of Africa. And so there what happens in that population is they tend to, when they drink milk as adults, get very ill with it.

And there'll be people in this country who have the same symptoms. They can't drink milk. and that's simply because the enzyme is not expressed. So they don't have that enzyme, it's been shut off. In most animals, humans are unusual, or white Europeans are unusual. And that enzyme is still expressed in adulthood. It's still available to your body. But in most populations and in almost all other animals, it's not.

You don't need it, so you don't use it. But we've adapted to be able to break apart the bond of lactose as adults. That's why we can survive in cow's milk. Another example would be where we use a chemical, to take away an enzyme. So you can think of medicinal benefits, so like Viagra. Viagra shuts down Guanate cyclase,

which is an enzyme and allows men to sustain an erection, or older men to sustain an erection when they lose the activity. Or you can use it as a chemical agent. So organophosphorus, these nerve gases, they shut down an enzyme called acetylcholinesterase, and of course you die in seconds from exposure to nerve agents. So there's always always.

been that side to taking away enzymes. Some of them we don't have or we lose, and some of them we be modified with chemicals. Most drugs work by inhibiting enzymes. So they're inhibitors, aren't they? Yes, we give inhibitors and we sometimes lack enzymes so we can smoke grass, but we can't eat it, because we like the enzymes that break the bonds in grass. That's a very specific chemical reaction that we can't do. Sarah Barry, what we've mentioned in a rather jocular, trivial fashion, the speed at which these things are going, can we develop that a bit more and say why it's important? Well, it's important. So it's important because it's important is what the biological context of an individual enzyme is.

So people have already mentioned this, but in terms of how fast an enzyme goes, it's not that an enzyme has, every enzyme has to be incredibly fast. it has to be fast enough to do the job in the situation that it finds itself. Can you give us an example of some of the jobs? So I think, so for example, if you have a process in the body that results in the production of a toxin, so some people might be aware of things like free radicals, right? So these are damaging to the cell. And what you have is a number of enzymes within the cell that are able to act incredibly fast.

So we refer to them as diffusion controlled enzymes. So as fast as they can identify, come in contact with the substrate, they will turn it over into something that is relatively benign to the cell. And that's incredibly important. That has to be that fast in order to protect the cell. So they're like fire engines. Yeah, exactly. They're rushing around.

Yeah, rushing around, putting out fires everywhere, exactly. However, you might have another system where they're, and this is very common in pathways in cells. So lots of cells are, most of the processes, within cells are divided into pathways or cycles. And so what you have is a series of enzymes that work in sequence. And there's no point in one enzyme working faster or too fast to accept the substrate that the previous enzyme produces.

So everything has to work at the right speed to produce the molecules that then move on to other processes. So that's all very finely balanced. It's not always that those enzymes are working as fast as they could do, but they're working fast enough to do the job in that particular context. So that's an extremely good point. The rate of an enzyme, when we always talk about these huge effects on the rate of a reaction, we're really thinking about the maximum rate.

And there are some enzymes, as pointed out, that certainly the enzyme that controls your blood pH, or your blood acidity, is working as fast as it can possibly work. But within a cell, most enzymes can't work at their maximum. right, because their starting material, the chemicals they need to process are not present enough in high enough concentration. So there's a balance. So imagine it like this. You could be the world's fastest toffee eater. But if I don't give you any toffee, you can't eat toffee, right? You can't process toffee. So the rate at which you work is a balance between what you can intrinsically do yourself, which is your maximum rate,

and the amount of toffee you have available to you, which you can actually process. And that amount is being controlled by other enzymes in the cell, which are all working together. And those amounts are very carefully regulated. And this is, of course, how you get dynamic effects. This is why cells can respond to changes. Because if enzymes are always working at their maximum rate

and the environment changes, how can the cell respond to that? So in fact, enzymes are working at usually about half their maximum rate. And then if the cell needs them to work faster they can by making more of the chemicals, the cell can slow them down. In fact, the cell can switch them off. The cell can do many different things to affect

how fast an enzyme carries out its chemistry. You're talking in terms of terrific intelligence, aren't you, really? Well, that's also dangerous, say. It implies intelligent. I'm not trying to be dangerous. I'm trying to find things out. I mean, it sounds very intelligent to me, extraordinary. Is it a better word? Evolution shaped us.

Well, isn't evolution intelligent? No. I don't think so. I mean, it just does enough to survive, I think. Well, that's quite intelligent. But there's no part. Let's drop it. Okay, fine. But I think to get at what you're saying is, what has happened for cells to function,

you have to develop control, mechanisms. You have to have feedback loops. If something is not supposed to happen, you have to switch it off. Sarah, do you want to come back on that? No, I'm more or less agreeing with Nigel. When we were kids, you used to

be able to do this experiment in school, maybe kids have, you did it when you were at school, if you take peroxide and you take a prick of your blood and drop it in and it foams and that's because you have an enzyme that breaks apart peroxide, which is, as Sarah said, one of these touch and go enzymes that's diffusion limited and because

peroxide is really poisonous. We generate it as a byproduct of breathing. So we can't avoid it, but we need to get rid of it very, very quickly. And you have a fantastically active enzyme in your blood called catalys. And we used to do this at school. You just stick a needle on your finger and drop a bit of blood and it foams up. Can we keep talking about these? Can we talk about versatility in actual? How versatile are this? Is there one enzyme for what Jim's just talked about?

That's its speciality, or what? So it turns out that So the dogma is that one enzyme molecule will catalyze the speed of one reaction using one starting material or one component to do the chemistry. That's the dogma.

In fact, many enzymes sometimes make mistakes because of issues in their structure and in their motion. And many enzymes will actually catalyze one reaction very well and a second reaction quite badly, a related chemical reaction quite badly. And this is very important for evolution

because what happens, if you want a new enzyme catalyzing a new reaction, how do you get that enzyme? Where does it come from? Does it just form and you get lucky? Well, maybe that happened in the first beginnings of time, but now there are so many enzymes around as templates that evolution can duplicate the genes

and it can change the structure of these enzymes. I'm being anthropomorphic, but I don't intend to be. This is a purely random process about how enzymes get optimized. And then the second activity, which was very low, actually the structure changes so that now that activity is the major activity. and now you have a new enzyme catalyzing a new reaction. And so enzymes are quite versatile.

They do have these small secondary activities and we can make use of those to develop new enzymes capable of doing new chemistry. But in general, yes, for a given reaction, there will be one enzyme that catalyzes that reaction. So can we develop that, Jim? Can you manufacture a new enzyme? easily now as things developed so quickly

how do you know you need a new one? Ah well so evolution shapes the need for things you can see is Nigel explained the process and it will be when it takes time but bacteria do this type of trick for example when they get exposed to antibiotics

one of the things they'll do is they often evolve strategies to destroy the antibiotic so they will evolve an enzyme based on one they already have that's optimized to destroy the particular antibiotic that you've just given them. And they do that in response to the change in the environment because all of a sudden, if they don't break this apart, they die.

And so that drives that evolutionary change very, very quickly. Sarah, what happens then? Can we go into it? When scientists, you people, try to adapt enzymes by changing their structure, I mean, is it a time to say how you can do that? It sounds extraordinarily difficult. Yes, no, no, it's actually not that difficult. So there's a couple of reasons why we might want to do it. So one of them is actually to understand how an enzyme works.

So to study the function. So we mentioned earlier that enzymes have an active site. They have like a pocket almost where the substrate is recognised. The substrate being... Being the molecule that it acts upon. And we may decide that we want to change particular aspects of that active sites by switching out one amino acid for another amino acid that points in and interacts with the substrate molecule.

And by doing so, we can understand something about how the substrate interacts with the molecule and something about how the chemistry works. And that's relatively straightforward thing to do. And that's a common research tool in terms of studying enzymology. What we can do is extend that. That's a very rational approach. So we take the technique that Jim talked about earlier, how you determine the structure of an enzyme. We look at the structure and you say, right, that position looks interesting. And we change it and do the experiment.

unfortunately we don't understand as much as we would like. So this targeted approach of looking at the active site in many ways is the low-hanging fruit because that's where the chemistry happens. But as you move out, proteins are much bigger than that or the enzymes are much bigger than that. So there's all this other stuff around the active site. It's holding the protein together. But actually it also has some very nuanced effects sometimes. So where we utilize this, so by changing enzymes that are far away from where the chemistry is

happening or changing amino acids far away from where the chemistry is happening, often has knock on effects that we don't expect. And those knock on effects often are things that we don't quite understand because enzymes are not rigid structures. They are dynamic. They change in the course of the catalysis that they're doing. And the nature and relationship between catalysis and structure is something that's hugely important and something we don't properly understand. But what we can do is take advantage of evolution by using a process called directed evolution. So that's where we basically randomly mutate the enzyme, randomly change any position. We don't have any bias.

And we make different versions of the enzyme and we test them for the activity that we want. And we go through multiple iterations like evolution until we ultimately identify an enzyme that has the properties that we would like it to have. So catalyzing a new chemical reaction, for example. So to use the word intelligent isn't very intelligent because it's not intelligent at all. It's completely only screening for the activity that you might like to have. So, for example, you might want to catalyze a new reaction. It's withdrawn from the previous part of the conversation.

Jim? As Sarah said, we just don't yet understand enough really to rationally design an enzyme. It would be equivalent to asking somebody from 100 years ago to redesign a computer. We just don't. The enzymes we are learning all the time and they're a constant surprise, but we just don't understand enough to build one ourselves. Yeah, so essentially, if you come to me and you say, here's a chemical reaction I want to happen. Say you want to make a new kind of plastic, okay?

Then if I cannot sit down with any technique that I'm aware of, any computer, and just design an enzyme from scratch. But what I can do is I can look for an enzyme that catalyzes a similar reaction. And I can then essentially replicate evolution in a test tube. I can make thousands and thousands of different molecules, each of which has one tiny change, and I look at each one of those molecules in turn until I find the one that will catalyze your chemical reaction.

Then I will take that molecule. I will make another library of molecules from that enzyme molecule, a library of enzymes, and I will look through them. And this sounds like an incredibly time-consuming process, but actually with the methods we have in the lab, these days, you can probably do it in between three to six months. A year if you have a really

difficult problem. This is becoming almost routine. Jim, can we take one, I go away from us, example, away from humans. What does the action, how does penicillin relate to enzymes,

for instance? Yeah, that's a really good question. Penicillin is such an amazing molecule, right? We're large. It's one of the seminal discoveries of the 20th century. People used to die all the time from infection, childbirth, all sorts of things that happened to us. Penicillin enters bacteria

and it prevents them making a very specific crosslink. So bacteria crosslink, what's called a peptidoglycan, they stick together two amino acids and crosslink, it gives them all their mechanical strength. Penicillin reacts with the enzyme and irreversibly modifies it so essentially puts a spanner into

the enzyme and it's dead. And without that, then the cells become incredibly fragile and burst. And it's a beautiful chemical reaction. It's very simple chemical principles that's based on something called a beta-lactam ring. But bacteria were playing this game against one another for millions of years.

Most antibiotics come from bacteria fighting one another in the game of survival. You say that bacteria are better chemistry than you are? They are, absolutely. Humans are very lazy chemists. So we go around you. eating plants and animals because we can't make the wrong materials ourselves. Yes, I mean, that's an extremely important point.

Not all organisms can catalyze all possible reactions. So human beings have specialized. We've reduced the number of reactions that we carry out to a relatively small number. So if we want molecules, new kinds of molecules, we cheat. We go and eat things with those molecules already in them. Okay, that's how we cheat. That's why we can do less. Yes, that's right, eating and cheating.

Brilliant. Because evolution meant that we could focus on other things, and that's why in your corn flakes packet you've got all these vitamins. So we know like vitamin C, for example, if we don't have vitamin C, we get scurvy. But we can't make vitamin C. You know, you could eat the raw materials from now till doomsday, and you'll not make a drop of vitamin C. So we need to eat fruit to get vitamins.

Folate, people will know if they're expecting children. All these vitamins are just, vitamins are another name for molecules we can't make. Sarah, what applications do enzymes have in industry? Oh, in industry? So, I mean, as we've already heard, we've been using them for thousands of years to make bread and beer and wine and that kind of thing. But also in other, I guess all I would define as digestive processes.

So paper, making paper, paper pulping, enzymes are used in that. So where you have a very tough raw material that enzymes will often help process that break it down into something more usable. So in the processing of plant material like corn to extract sugars from the corn, enzymes will be used to help break down that tough part of the corn to help extract the sugars. So that's very big, bulky, industrial chemistry to obviously to extract relatively low-value chemicals, if you like. What's, I think, more exciting and what Nigel has already talked about is this idea of using enzymes to make complex molecules.

And I think this will be something new. This is the future of biotechnology and the use of enzymes. So as you've already said, bacteria and enzymes are better chemists than we are. And they can catalyze reactions in a very specific way, in a way that is very difficult often for us to do using traditional synthetic chemistry. And also, they can do it in water. So in principle, then you've got a more sustainable way of doing chemistry. And this is also a driving force to moving.

towards this. Nigel, how might enzymes revolutionize chemistry and therefore have a knock on effect into industry? Well, so this comes back to what we've already started to discuss. Making complicated chemical structures is difficult. It's expensive and it's time consuming. And many times you will get mixtures, you'll have to purify compounds. It's very difficult. So an example of a molecule recently, which you may have heard of, is called artemisinin,

which is an anti-malarial compound. I think the Nobel Prize was given to the discoverer of this compound last year. Now, this is a very difficult compound to make in the chemical laboratory. But if you could make a kind of intermediate, it would be very simple to take that intermediate and convert it into the final product. what we can do is we can take the enzymes from the plant, which makes that intermediate, we can put them into bacteria, we can then re-engineer how the bacteria control whether those enzymes are switched on, whether they work, and now we give the bacteria the ability to do new chemistry to make the molecules we want.

Another example, and then I'll shut up, which is plastics. You want biodegradable plastics, right? it turns out that there are some bacteria which actually make plastic for reasons I have no idea why they make plastic but they make plastic you can see them making the plastic inside themselves we can take those enzymes we can modify their structure we can put them back into the genes back into bacteria and now we have bacteria that can make new kinds of plastic

and the plastics that they make because of the chemistry they use means that the plastic is completely degradable after you've finished using it because of the chemical groups in that molecule have a specific structure that other organisms can use and they can break down and use those molecules for something else.

Brilliant bacteria then. Yes, absolutely. Can I ask one side? Sorry. No, no, go ahead. Jim, can I ask you one side question if you could be brisky about this because I'm fascinated.

This isn't very long that this has been studied, not really, in any time scale, 120 years, something like that. What's come on in the? the technology that enables you to go so quickly, it enables you to get to grips with it at such depth? I would say the biggest change has been

molecular biology. What's to stop you? What's the technical stuff? Our ability to manipulate DNA. That's been the key part of this, is that we've all tried to say that we don't really understand enough about them. If we just to study them as they were, we would really struggle. It's our ability to

manipulate the enzymes directly using our chemical, human imperfect knowledge to adjust the enzymes by genetic engineering has been the huge. I personally would say the biggest breakthrough. And does this include very well-developed? I'm really ignorant here, I really want to know. I are sitting in your laboratory with massively enhanced microscopes, this, that and the other.

What's the stuff you're using? So one example would be gene sequencing. So our ability to sequence DNA, in the last 10 years alone, I mean, it used to be able to, it would take you years to sequence an entire genome. Now we can do it in, you know, a matter of a week. And we can see structures of enzymes much easier now than we could,

even when I was a graduate student, that we can see, and as a chemist, you look at an enzyme and it tells you something about the chemistry. And that ability to see all the atoms is changing how we think about enzymology, and I think that's the other revolution. Absolutely. And then, you know, the other big thing that's happened in the last 15, 20 years is robotics. So now there's been a huge automation of very basic techniques, laboratory techniques,

which would be quite slow if people did them. And you could do one experiment, far by one experiment. Robots can carry out thousands of experiments simultaneously. And so you can shorten the time to making the enzyme and studying in the enzyme. enzyme. I mean, things that would take a PhD for three years now could take someone probably, I don't know, three weeks, a month. We could have you doing it in three months, tops. That's all it would take. I promise you. You couldn't. But thanks for the compliment. I treasure that. Jim, you've described enzymes as, quote, the most interesting things known.

Yes, I would absolutely see that. Quickly. I'll give you one example. The fluorinease molecule makes a carbon fluorine bond. And yet that is one of the most chemically difficult things we can accomplish. It's incredibly useful for pet, but just as a chemical process, it's fascinating. There's an enzyme exists for making that bond. That bond, that's why you have fluoride in your toothpaste. You could eat it all day, all night, and you won't make a carbon fluorine bond. It would take the lifetime of the universe, and there's an enzyme to do it.

That's such a unique, amazing bit of chemistry. How is it going to, that's one example. How is it, in general, how are enzymes helping medical science are? So we've already talked about penicillin. So one of the most common, important aspects of enzymes is their targets for drug discovery. So penicillin, HIV proteases, for example, the drugs that we use to treat HIV, a lot of them inhibit this protease that enables HIV to make new viral particles. So it stops that process, stops the replication of the virus.

Aspirin. Every time you take aspirin, you're inhibiting an enzyme. So you're stopping the small molecules that mediate pain from forming, from being produced. So it's all enzyme inhibition or inhibition of key processes. So enzymes in your body are key things that need to be inhibited by drugs. And so they're important in drug discovery. Well, thank you very much. I'll look at myself with more respect, in Fisher.

Thank you very much. Sarah Barry, Jim Ney Smith. and Nigel Richards. Next week, we'll be discussing the medieval author Christine de Pizan said to be the first woman to earn her living from writing. Thanks for listening. And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Melvin and his guests. So what did I miss out? Is that...

I thought you were great. Well, I think you missed out the importance of enzymes in plants. There was a question, but there wasn't time. I can tell you, I show you the question. Yeah, I'm sure. Well, you can ask me the question. Ask you the question. What about enzymes in plants?

So, you know, all of the sugar molecules in the world. So, you know, the important thing about plants is that they consume carbon dioxide and they make sugars, which we use for energy generation, and they make oxygen as a side product of that reaction. Okay. The enzyme that does this chemistry that allows you to take carbon dioxide, molecules which are very unreactive. They don't really do chemistry and connect them together was invented once in bacteria hundreds of millions of years ago and then was given to other organisms like plants where it became kind of optimized for use. Fantastic. Ammonia, fertiliser,

that enzyme which takes nitrogen in the air which is completely unreactive and makes ammonia, NH3, which is one of the most important chemicals in our society, was invented once because the chemistry is so difficult. Again, cyanobacteria, then into plants, so that plants basically can provide the raw materials for all of animals. Did you also say that oxygen was invented once? No, no. So oxygen is an element.

It's been there in the universe. But the enzyme which generates oxygen. That's it. Which makes oxygen from water. uses an incredibly complicated chemical reaction that we still don't understand. And it was made once in the whole of the Earth's history.

And importantly, we still can't replicate. We cannot replicate. The question that, I mean, it's a really raw question, but it's invented once. Why did it catch on to be invented again? I mean, you haven't once it could have missed it. Billings and billions of things. No, no.

So the enzyme got invented once. In other words, the DNA sequence, encoding that molecule got made by chance at the beginning. That DNA was then other organisms can swap DNA. So bacteria, you know, so the gene got transferred to many different organisms and then it's replicated and in those organisms it's optimized. I get it. But there was only, it was only invented once.

Some enzymes to do simple reactions, you can see they were invented. The genes were invented several times. evolution completely independently. We can, we can, we know that this happened. This is one thing that we're always very careful of when we ever talk in the public sphere because this idea of intelligence

is very seductive. It's how I often maybe talk about it with colleagues, but we're very careful not to use it in a public sense because... I just didn't. No, but you saw that... I was true. I'm a call it. It's, no, no, it's the...

It's a really, you know, you think of it that way because that's how we all think of it that way, but of course, we've got to be very careful that we don't go into intelligent design, which is law nonsense. And that's why people worry about, but when you think about them, they are beautifully designed, but they're not intelligently.

The complexity is seductive, and I think it allows you to think of the idea of design, but it's, of course, it's not always optimal what happens in a cell. I think that's the important thing to remember. It's just good enough. It's just good enough, exactly. I think one of the other things that we missed out on, and because we mentioned a couple of compounds that, because I enjoy talking about this,

but we've mentioned penicillin and artemisinin, which are both compounds that come, that are medically used and ultimately come from the environment. So one is produced by a fungus, penicillin, and artemisone is produced by a plant. And it's important that they're both complex molecules exceptionally difficult to synthesize,

and the way we produce penicillin, we still produce a bi-fermentation of the fungus. We do not make penicillin because it's too hard to make, and if we did it, it would be too expensive to use. So we rely on the fungus to make it for us. The same with artemisinin. Synthesizing it would make it too expensive to use as an anti-malarial. And so we either rely on the plant to make it for us or we want,

because extracting things from plants is not easy. It's also growing enough plants to produce the artemisinin as quite land intensive and so on. And it can be affected by drought or whatever. And so using this engineering approach with bacteria that Nigel mentioned is one way of us kind of making it more sophisticated, I guess. But ultimately, we're relying, as you said, on organisms being better chemists than we are. So the other thing we missed out actually

as of no practical use whatsoever, which is, I'm fascinated by it. Because we have so much information about the structure of enzymes and how the structure changes from organism to organism, we can actually figure out the sequences, the structure of enzymes

that existed 100 million years ago or 200 million years ago or 300 million years ago and we can make those enzymes again in the laboratory and we can find out what they did and so we can begin to understand not only life now but what life was doing back there when the dinosaurs were roaming around the earth

we can actually begin to understand how things which existed millions of years ago did chemistry. Amazing. I think if we could leave with one point that we'd all agree on is that the chemistry of the bacteria do is maybe that message came true it's fascinating they've been fighting one another for a billion years

and the penicillin comes from this game when you take augmenting there's another compound there called clavulinic acid that inhibits the ability to break penicillin so bacteria already have their own antidote to penicillin and we now use that to treat drug-resistant bacteria, you give two compounds. And they do so much chemistry. They make so many exotic molecules that have weird and wonderful effects,

and they're so good at it and just amazing to study. I think here comes a producer to make you an offer you can't review. Just tea or coffee for you. Oh, very much, sir. There are many more science and discussion programmes from Radio 4 to download for free. Find these on the website. website at BBC.co.com.uk slash radio four.