In Our Time - The Origins of Infectious Disease

Episode Date: June 8, 2011

Melvyn Bragg and his guests discuss the origins of infectious disease. Infectious disease has been with us for millennia. There are reports of ancient outbreaks of plague in the Bible, and in numerous historical sources from China, the Middle East and Europe. Other infections, including smallpox, tuberculosis and measles, have also been known for centuries. But some diseases made their first appearances only recently: HIV emerged around a century ago, while the Ebola virus was first recorded in the 1970s.But where do the agents of disease come from, and what determines where and when new viruses and bacteria appear? Modern techniques allow scientists to trace the histories of infective agents through their genomes; the story of disease provides a fascinating microcosm of the machinery of evolution.With:Steve JonesProfessor of Genetics at University College LondonSir Roy AndersonProfessor of Infectious Disease Epidemiology at Imperial College LondonMark PallenProfessor of Microbial Genomics at the University of Birmingham.Producer: Thomas Morris.

This BBC podcast is supported by ads outside the UK. Thanks for downloading the In Our Time podcast. For more details about In Our Time and for our terms of use, please go to BBC.co.com.uk forward slash radio four. I hope you enjoy the programme. Hello, in his history of the wars, the historian Procopius of Caesarea records a dreadful event which befell Byzantium in the year 542.

At this time, he wrote, there came a pestilence by which the whole human race was nearly annihilated. It said that half the city's population died of bubonic plague in perhaps the most serious outbreak of the disease before the black death ravaged Europe in the 14th century. Plague and other infectious diseases such as leprosy are documented in ancient literature and have apparently been with us for millennia,

but others such as HIV and Ebola have emerged only in recent decades. So where do infectious diseases come from and how can we trace their origins? Procopius believed the plague he documented had begun in Egypt, Modern DNA techniques suggest that in fact it originated in China. With me to discuss infectious disease and its origins are Steve Jones, Professor of Genetics at University College London, Sir Roy Anderson, Professor of Infectious Disease Epidivology at Imperial College London,

and Mark Palin, Professor of Microbial Genomics at the University of Birmingham. Steve Jones, let's start with a specific example. The plague of Justinian, which I mentioned, is known medically as the bubonic plague. What causes that and where did it come from? Well, that's in fact of 541, as I remember. The plague of Justin is the first real account we have of a massive disease in historic times, although the Bible talks of earlier plagues, which might possibly have been the same thing. It's caused by a bacterium.

It used to be called Pastella Pestis after Pasteur, but it's now been renamed as the Yusinia pestis. And it's an interesting disease, first of all, because it's so lethal. It often kill half or more, the number of people who infects, often very quickly. It spreads very quickly, and like many diseases, perhaps all diseases. It comes from animals. And it comes from animals that are all around us,

particularly the rats of different kinds and Marmot in Central Asia. And for some reason, at that time, it took off. And that's what happens with many of these diseases. They suddenly explode. And if you look historically, even through biblical times, you can see that Babylon, then the world's largest city, people used to hiss at Babylon because of its diseases. Why was that? Because it was a big city, lots of contact between people, a big reservoir of individuals to infect,

so that various plagues, in the general sense, could take off and spread. And, of course, we now all live in one huge interconnected city throughout the globe, which is why we have these global diseases like HIV and the others you mentioned. Can we go back to the bubonic plague? And can you just tell listeners how that might have arrived there in 541, and then it recurred in medieval Europe. We might get to that later. Yes. It's still there, the plague.

It has reservoirs in animals, as I said. It's carried by fleas that live on those animals and then bite human beings. Nearly all great epidemics have coincided with social changes, and the great plagues are among them. It's noticeable that as empires grew, the Roman Empire, for example, as you mentioned, then epidemics grew. And you can see that particularly in China, because in China they kept fantastic rations.

records from more than a thousand years, it should be more than a thousand years, from the beginning to the end of Imperial China. And they record the population growing, did the spread of disease, and suddenly population reaches a certain level, movement reaches a certain level, and huge plagues get going.

There was a massive plague in China after the plague of Justinian, which killed half the Chinese. And that's when Chinese cities, Chinese movement, the Chinese economy, got moving, and the plagues got going. very often these new diseases coincide with a change in our relations to animals.

Rats in city, shall we say, or domestic animals, and many domestic animals have given rise to such diseases. Plague is actually rather unusual than it comes from a pest. Humans, we've been on this plan for at least 200,000 years. Has infection been, infectious diseases been? I think in some sense, yes, I often think that history you can divide into three great epochs,

the age of disaster, which is 99% of all history, when people were killed by Sabertl Tigers or they starve to death, the age of disease, which happened when population numbers went up, and we had these epidemics. And now we, in the Western world, at least, are in the age of decay, when people actually don't, generally speaking, die of infectious disease, but die through their own intrinsic inability to stay alive through decay. But the age of disease was with us for 10,000 years from the beginning of agriculture,

and in most of the world, of course, it's still with us. Mike Palin, agents of infection, infectious diseases are known as pathogens, the best known of viruses and bacteria. Can you begin to tell us something about those? Okay, let me start by giving you the standard answer, and then I'll qualify that. So the standard answer is that bacteria and viruses are actually quite different things. And microbiologists get very upset when they hear people talking about the E. coli virus

or the MRS virus, because those are in fact bacteria. They're not viruses at all. Bacteria, like us, are made from cells, their cellular organisms. They're different from us in that they're unicellular, whereas we're multicellular. We're made lots of different cells and lots of different kinds of cells, whereas for the bacteria, the cell is the organism, more or less. Their cells are smaller than our cells. They also package up their DNA differently. We have our DNA packaged up in a little bag inside our cells called the nucleus, whereas bacteria don't have that.

They just have the DNA kind of hanging loose in the cell. In fact, in the jargon we call our kind of cells eukaryotic cells because they have this nucleus and those of bacteria called prokaryotic cells or prokaryotes. We know that there's also some other kind of prokaryotes apart from bacteria called Archaia, which have recently come to prominence sometimes called the third domain of life. And it's an interesting observation that they don't actually cause disease at all. It's a bit of a surprise why that should be. When it comes to viruses, we're looking at something different.

smaller than bacteria, but they're also not cellular. If a bacteriologist wants to disparage viruses, he calls them just infectious chemicals, because they are much simpler. And when they're outside the body, they're inert. They're metabolically inert. There's no chemical reactions going on. They can survive in that inert state for long periods of time, but they're not doing anything. And to do anything, they actually have to get inside cells and hijack the cells and use the cells to make more copies of themselves.

How do they do that? Well, in particular, what they do is they have to take over the control of the protein synthesis apparatus. How do they get in the first place? How do they get into the cells? There's a variety of methods that they get into the cells. They usually attach to the outside of the cell. I should actually point out that when we talk about viruses, viruses can infect human cells and other eukaryotic cells. They can infect bacterial cells.

They can even infect archaeal cells. And each different kind of organism has different kinds of viruses. And so the strategy is used to get inside the cell. or vary depending on the kind of organism you're looking at. In bacteria, there are very sophisticated mechanisms for injecting DNA and so forth. In human cells, there are different mechanisms where the cells get taken up? But are viruses in the air we breathe and that sort of thing? Well, viruses are in the air we breathe.

If someone sneezes in the room, there are viruses there. People have been looking, actually, taking a fresh look at where viruses are on us and in the environment. And they've been absolutely astounded that there are so many viruses out there. If you look in the oceans, the oceans are just teeming with viruses. And when you look in, say, the human gut, people have, or in, say, in the lung of a cystic fibrosis patient, you find absolutely huge numbers of viruses. When you use, there are these new methods,

culture-independent methods that use DNA sequencing. And it's remarkable that we're just swimming in a sea of viruses. And it's, in some senses, you can argue that viruses are the predominant life form. That's one argument. The other argument is they're not a life form at all, because they don't live in the way that we do. There are other pathogens, they're worms and fungi and so on, but if there's all these millions of these things in our gut

and in the ocean and everywhere, how are we so effective in resisting them, some of us some of the time? Well, there are several answers to that question. I mean, the kind of physiological and anatomical integrity of the body is important there. So the fact that you're clearing your throat, you're blowing your nose, you're passing urine, your guts are working normally, all of those things are actually flushing pathogens out the body or potential pathogens out of the body all the time. And if those things stop working, as we sometimes see in hostileised patients, you can get things bung up and then you get infections.

But we also have a very sophisticated immune system with two components. There's one that's kind of a generic, so-called innate immune system. that is on the lookout for all sorts of things. And then we have the so-called adaptive immune system, which when it sees something the first time, starts to kind of make a memory of that, and then recalls that memory at a later date, and it is actually able to very effectively deal with that pathogen

when it sees it a second time. So the beginnings of the immune system kick in as soon as we're born. Yes. And the longer we live, the stronger it is on the whole, because the more experience and the longer memory has of fending off these attacks. On the whole. On the whole, in old age there is a decline in immune function as well.

But yes, generally as you mature, particularly neonates do have an immature immune system as well. We're still not. Can you just briefly before I remember. So there's all that and there's all that and there's all that. But why these sudden mass attacks, what happens then that Steve was talking about? Right. So it's worth just reflecting on what kinds of infections we have. where they come from.

I'll quite like just to stick to the buponic plague as a specific example and then move on. Okay, so those kind of infections have actually moved, as Steve pointed out, they have moved from another host into humans usually. And when they cross over into a new host, they adopt a new kind of behaviour, which can be dramatically different from their behaviour in their original host. So the immune system isn't ready for it? The immune system is not ready for it.

And behind the immune system, there's all kinds of things like inflammatory response. and all those sort of things which can get called in, called down upon by these new agents in a way that's not appropriate. So to be specific, sorry, it's the newness of the switch in the nature of the virus that takes the body by surprise and people are not ready for it. So half the population of Europe is wiped out in the middle ages because of that. So what happens is that when a new agent comes in after a period of time, you do get the evolution of genotypes in the human population

where people can actually respond to it and survive it. Thank you. Roy Anderson, we've probably known about this microbes since the 19th century. How are they discovered and were there any particular individuals involved? Well, it's quite an interesting history. We've certainly go back to even Darwin commented about spores in the air, which he thought might be the cause of disease. but the real sort of change period for science was the Pasteur and Cock period in the 1800s

and methods and techniques were developed to the microscope was important looking at things, very small things, but more importantly the ability to grow them in culture and then see whether they infected experimental animals. Today of course we have a most extraordinary array of scientific techniques and were able in the human body to detect very small numbers. numbers of viruses or bacteria. So if you look at our very rapidly changing world today... Can I just pause your...

I think people would be interested to know how this thing got going with Pastor because it was an very important development. As Steve pointed out, at the beginning biblical times and pre-biblical times, plagues and so on, and then they found out what was really going on. Can you just tell us a little bit more about Louis Pasteur? Well, Pastor was an experimentalist and a very sort of broad scientist at his time. 19th century. Yes, and he was interested very much in what caused disease,

as many people were at that time. There were many individuals who'd written throughout the centuries that it must be some small organism, spore. And Pasteur started to look for these small things and found bacteria, and then he found they grew in culture, in a broth, and then he also found that he could infect animals, and consequently they caused disease. The next stage in the history, working at roughly the same time, was Cock,

who developed a set of rules called Cock postulates, which define an infectious agent, and they are that you can identify it from a disease person, you can extract it, you can culture it and grow it, you can put it back into a person or an animal, and it causes disease, and then you can extract it again, and there's four principles. So that was the beginnings in around the 1860s of the discovery of infectious agents. is much more recent. We're talking there because they're very small,

and indeed they're sort of primitive. That was more in the 50s, 60s, probably starting in the plant virus area, and then moving over to humans. So we have this investigation beginning and obviously then proceeding a pace in the 20th century and into this century. Is it possible at this moment to generalise where most of these pathogens, these microbes, these viruses come from? Yes. Well, you mentioned yourself that as a subspecies, Homo sapiens, we are probably a few hundred thousand years old. Homo sapiens, as a broader genus, is about half a million years old.

We probably acquired all our infectious agents originally from wild animals and then more recently from livestock. We acquire from them. We probably pass a few back to them, but they don't have reporting systems that detect these events. and if you look at modern times you can see that HIV came from chimpanzees How precisely from chimpanzees?

Pretty precisely now you can... So how did it work? How did the chain work? Chimpanzees acquired it from monkeys probably many thousands of years ago. By what, biting monkeys or what? Yes, biting, eating monkeys and so forth and then the bushmeat trade

where chimpanzees are shot in, say, the Congo and then eaten as human food. perhaps not cooked very well. The inside of our mouth has lots of little abrasions on it, and undoubtedly the blood from the chimpanzee, which carried the virus then came into humans. This event was quite recent. It was probably 1920-ish, somewhere around there.

Malaria, which is another very important... Let's stick with Edgwick, because it's interesting story, because it was at that time local, wasn't it? Well, if you take the history... So we have it there. Yes. When does it begin to move? How does it then move around the world?

Well, Steve mentioned. a point about in the early societies about aggregation and movement. Our changing world today has four facets which are hugely valuable to infectious agents. The first is travel. Geographers tend to describe things called lifetime tracks, which is an individual's spatial footprint on the earth throughout his or her life. And if you take four generations of the same family, the great-grandfather probably walked locally between villages.

The grandfather probably went by coach and horses between counties in England. The father, say it was the Second World War generation, travelled influenced by conflict, but then the beginnings of tourism, going to Spain and Europe and so on. And then the current generation is a globe trotter. It goes all over the world by air travel.

So in four generations of our species, and our species has only had about 20,000 generations, we've changed from a very local animal to a global trotter, and that has moved the local evolution of infectious diseases to encompass the world. We have other facets. So come and go back to the chimpanzees? Yes. So the chimpanzees are eaten as meat in Africa,

and then travel begins to distribute this around the world. Is that what happens? Exactly that. So 1920s travel and communication and networks of roads or rails were very limited in Africa. They've expanded greatly. so the virus moved slowly out from the 1920s, and we first noticed it in 1981 when the disease AIDS was diagnosed. Now, how do we know this scientifically? We know the genetic code of the virus, and we can work out approximately its age in its current form by looking at the rate

the genetic code changes over time. There are other facets of human societies which promote infectious disease. Our modern world is a very different world, so it's travel number one, Number two is population size. We're up near to 7 billion, perhaps 9 billion by 19, another by 2020. If one looks at population has two effects. It improves the transmission of infectious agents. Each transmission event, though, is an opportunity to evolution. So population size increases the speed of pathogen evolution

and increases their transmission efficiency. So I mentioned that Homo sapiens has only had 20,000 generations, a virus may have had a trillion generations during our evolutionary history. So their evolution is always much, much faster than us, and we are racing to catch up. Can I ask Steve to do the next two factors?

And then two have been mentioned, and two more to come, aren't there? Remar me all they are. I think both your papers have. There's travel, and there's the intensification of cities, and then there's animals and so on. Yes. I mean, the animal story, we've mentioned,

that effectively all diseases come from animals. In fact, the most dangerous animals to us are unsurprisingly our closest relatives. Things like chimpanzees. As Roy said, we know pretty much that they came from chimpanzees. In fact, we know almost certainly that the commonest kind of HIV came from a tiny area of Cameroon. But there are plenty of other cases where things have come from animals. There are diseases like measles, which is rated to the cattle disease, Rindapest, for example.

And what's fascinating really is a famous book called Guns, Germs and Steel, which I'm sure many of your listeners have read, which points out quite rightly that actually nearly all these diseases, these global infections are old world diseases. They're from, not from the Americas or from Polynesia, they're from the old world. And why is that? That's because animals were first domesticated in the old world. And the animals of the new world, like the llama, say the yama,

were used not particularly for food, but for wall and to draw, coaches and that kind of stuff. And in some senses, the new world experience of infectious disease is a microcosm over a century or so of the 10,000 year of experience which happened in the old world. Because when the explorers got there, they and their animals bought a massive disease, which killed 90, 95% of the population. Do you get much relevant information from historical sources, say from the plagues in the Old Testament? You do.

it's rather difficult I mean if you were to look back at the history of medicine it's worth remembering that medicine the practice of medicine stopped killing more people than it cured only in about 1920 I mean medicine used to be a dangerous pastime for the patient now things are different

and there were very very straightforward diseases there was a disease which was a real problem for everybody it was called fever you had a fever and the answer was always very clear you took a couple of pints away of blood away and that didn't cure the fever but it made it look busy. But of course, a fever is a symptom.

And there are many infectious diseases with the same kinds of symptoms. But if we go back briefly to the plague, there are some great writings from medieval poets in Wales in particular who talk about the swellings in the armpit. If you go back to the Old Testament, Book of Samuel,

the Philistines had a terrible attack of, what are they called emirods, and they're lumps. Now, that could well have, been bubonic plague, because bubonic plague, as we heard, arises from a failure of the immune system to cope with this massive

influx, and the lymph glands become swollen or lumps. So you may be able to identify some of these things, but there are many other diseases. There's a thing called the English sweat, which was in the Middle Ages. We simply don't know what they were. They may have come and disappeared.

Mark, how can genomics help establish where a disease came from? Well, there are two ways which we can use genomics and molecular methods, if you like. One is actually looking back in time and there's been considerable progress in the last couple of decades in actually getting ancient DNA out of samples. For instance. For instance, people have been able to detect plague DNA, the bacterium that causes play. You can detect that in samples that are hundreds of years old and maybe even thousands of years old. Can you give a specific example, a specific example in how you do it?

Well, so one of the pioneers in this field is a man called D.D.D.A. Raoul in Marseille, and what he's been doing is he takes the teeth from skulls, uninterrupted, uninterrupted teeth, and he drills into the pulp of the teeth. And that provides a kind of microcosm of what was in the blood of the patient at the time they died. And using sophisticated methods for amplifying DNA, he's been able to find plague DNA in some of the, what were thought to be plague victims by historical and circumstantial evidence, but he's actually shown that there really was the plague bacillus in there. In ancient Egypt in that case, isn't it? He's been doing it in France. In ancient Egypt, people have found tuberculosis in mummies,

and so you can go back that far. So that's one way in which we can use genomics. The other way is we can look at the genomes of existing pathogens, and we can compare them across the world, and we can look at their closest relatives, and we can come up with historical narratives as to what's happened. So to come back to the point about interactions with animals, one example here was with tuberculosis.

Before people started sequencing genomes, we knew that there was a human form of TB and there was a cattle form of TB in bovine tuberculosis. And everyone just assumed, well, humans probably caught it from the cattle when they domesticated them. But when the genomes were sequenced, it became clear that the cattle form of tuberculosis, tuberculosis was actually derived from the human form,

and it was we that gave TB to the cattle rather than the other way around. So that's an interesting example where we can reconstruct what's happened in the past and how these things have evolved. Now, Roy Anderson, can you tell us how this sort of technique is provided by the flu virus? What can we learn from its genetic makeup? Well, the flu virus is in all our minds all the time because they've been some of the most horrendous modern epidemics, 1918, coming forward.

If you think about pathogens, there is a sort of spectrum. At one end, there are very constant organisms who hardly change at all. And those are the ones that we've developed successful vaccines against like measles. At the other end of the spectrum, there's HIV, which is genetically changing

all the time. And I always liken it to trees, actually. The bottom end is a constant trunk. Influenza is just off the bottom end of a constant virus. The trunk of the coniferous tree has little branches that come off every now and again. Some of these are quite significant. They've changed the surface coating of the virus.

So the herd immunity of the current generation to its parents of the virus is lost and it can then exploit this virgin population that's all susceptible to it. So we understand quite a lot about the evolution of influenza, but what we can never predict at the moment because evolution is so chance-orientated is when a very difficult event occurs that the virus, which is endemic in birds and other mammals, pigs are a very important source of influenza, we can never quite work out when a change is going to occur

that's very important for humans. In other words, it's transmissible between people and it's also highly pathogenic. Very fortunately, the recent epidemic of H1N1, thankfully was a very mild virus, probably milder than the typical seasonal influenza. We have vaccines. We've talked about the bad things of the changing world.

We haven't talked about the good things. People often say that antibiotics were the great change in survival of human species after conflict injury or whatever. But my own view is that vaccines have been more important because in essence they protect the population against a specific type of pathogen. We've been hugely successful since the 1950s, in generating vaccines for all sorts of infections and immunising both rich and poor countries

with donations from all sorts of major organisations. So that's a success story. The holy grail for vaccines is to try and generate something which protects not just against one pathogen, but against a whole range of them. I think scientifically we have a glimmer of what we need to do, but it's exceedingly difficult task, and I don't imagine real progress to be made there for some time.

There was, is that what genetic evidence is there, how can we work out where the bubonic plague is at the moment, Steve? Well, it's still around. I think somebody died in the US just a year or so ago from ebonic plague. It's much rarer than what it is. And what we do, I mean, every pathogen, like every human individual, has its entire history encodular. it into its DNA. And by sequencing

that DNA, which we can now do at an astonishing speed, we can look at the relatedness among the various strains of, let's say, HIV, and also among other bacteria and other viruses in the living world. And we can make a tree of life, and that tree of life is remarkably

consistent. And one of the, if we go back briefly to the bubonic plague, what's remarkable about it is actually it's nearly all a single clone. There are some changes, but 99.999 5% of the DNA of the plague bacillus is the same everywhere. And what seems to have happened,

the reasons that we simply don't know, at some time in the past, just once a mutation took place, which turned this pathogen of small mammals into something that could live quite happily in humans. And that spread with astonishing speed. And what's amazing about the whole thing is as it spread, it picked up genes from other bacteria,

which allowed it to do jobs it couldn't do before. Is it capable of really? emerging? Oh, most sympathically, yes. The most dangerous kinds of disease are those which have a reservoir out there. The ones which we may have a chance of beating are things which are human to human.

And we've had great success, for example, with smallpox there. If we take the classic pair, I suppose, are typhoid and cholera. They're both waterborne diseases. Typhoid kills some people. There are plenty of people who have got the typhoid infection, who are not ill, but they infect others. Colour kills plenty of people,

but it's got a reservoir in small freshwater creatures. So even if we cure all the people, the reservoir is still there, so it may well come back. Mark, you wanted to come in. I was just going to say that Yusinia pestis actually is a very interesting example of what we can see in the genome.

So it started off as one lineage within a much wider lineage of bacteria that lived in the intestines, probably, and then acquired some new DNA which allowed it to live, to colonise fleas. And then a strange thing happened, it's also thrown away a lot of its DNA. And so if you look in its genome, you can see all these genes that are there but are broken. And it's because it's become very specialised now and hooked into this particular life cycle.

And it doesn't need all those things to live out in the outside world. And we see that theme many times actually with human pathogens. and so the organisms that cause typhoid or cause anthrax or pertussis, whooping cough, they're all having the same process where they're throwing away genes because they become so specialised they don't need them anymore. Oh, Innocent, what can our own genes tell us about the history of disease? Well, as you, and the listeners will know, the human genome, which is our genetic code, has been entirely sequenced now.

And we're in a phase scientifically where we're looking at variation in the genome, our genetic code in different people. If you look at the most variable regions, two of them are very interesting. One is our ability to recognise non-self. And the second region is a region which codes for the immune system, the immological genes. And that very strongly suggests it doesn't prove, but it strongly suggests that in our evolutionary history as a species, pathogens have been probably the major selective force until very recent time. It's modern medicine that has changed that.

But I come back to a point I hinted out earlier. People think that modern medicine will protect us going into the future. But my comment about our generations, our genetic change, is very, very slow, orders of magnitude slower than the pathogen, which is having, during our evolutionary history, trillions of changes. Pathogens will always outrunners. And if you take from discovery to when a vaccine gets to the pop. or a drug gets to the population, that's about 10 to 15 years.

In an emergency, I hope one could take that down a bit because it's regulation that makes in part at 10 to 15 years. So when something new emerges, and the coming century will see more novel pandemics than we've ever seen in our history. That's for certain, is it? I think it's almost certain it's because we're mixing globally, we're a bigger population density,

we have a more intimate relationship with livestock in many environments. So it's always going to be a battle between medicine finding a solution to a problem and the very rapid evolution. And when we do find a solution, pathogens can evolve so quickly, drug resistance is a good example, with antibiotics which was so important. We're almost running out of antibiotics at the moment for two reasons. There are some pathogens that are resistant to virtually all of them. And then secondly, it hasn't been a fashionable research area generating new antibiotics.

People have thought the problem solved. but if you apply a control whether a vaccine or a drug you quickly select in the pathogen for resistant strains and this war this sort of between pathogens and ours even with modern medicine is going to be a very intense and difficult one in the coming decays. Extraordered isn't it? Steve, Steve Jones, how is it possible? Can you give us a single example

for a pathogen to jump from an animal species to a human species? I think generally it happens by accident. I forgot the exact number, but there are scores of creatures that do infect us. One that comes to mind is the raccoon worm in the North America, which, too, it's raccoons, those little furry animals that run around, is relatively harmless. But what the animals do is that when they defecate, their feces get onto grass and that kind of stuff, children play, they put their fingers in their mouths,

and they become infected. The same kind of thing happens with dog parasites and children here. Now that can blind or kill a child, but it can't go on to another person. So I think we're constantly faced by a rain, by a positive blizzard of intruders who are just getting into us. Everybody, every time they eat a meal is eating a mountain of bacteria and viruses. Every time they take a breath is bringing them in. What's surprising, really, it's not how often these strange creatures get into us, but it's how rarely, how few pathogens we've got, and how often when they do get into us,

just one of them does and then flourishes. Mark. I was just wanting to tell you about a curious tale that's just published in the literature a few weeks ago. Leprosy is found in the southern United States of America, and Stuart Colony's group have been sequencing the genomes of lepros of lepros from humans and from armadillos. And the armadillo is the only other organism that can actually get lepros. And it seems that we gave lepros to the armadillos, humans gave it to the armadillos in the first place. it's now become endemic in armadillos in the United States but what they've shown is that contact with armadillos is a serious risk factor for catching lepros

so people who are going and catching armadillos and skinning them and eating them are actually getting leprosy back from the armadillo so it's an interesting example where we gave it to an animal the animal's giving it back to us Roy Anderson when a disease crosses a species barrier like that what happens next

well it's a sort of slow evil process. Influenza is not a bad example. HIV is another good one. To start with, the transmission is very stuttering because the virus or bacterium is very ill-adapted. Our immune system sort of attacks it very vigorously. And scientists have a way of describing this. A disease will begin to establish itself in the human population if each primary case of infection generates, on average more than one secondary case. If it's less than one, it stutters to extinction, if it's greater than one, an epidemic takes place.

Inside the human host, the virus or bacteria is replicating. It's under natural selection. So slowly it becomes fitter and fitter to actually penetrate one of ourselves, replicate inside it, and then get out again. So a lot of intense selection, every time a person is infected with the virus or a bacterium, a lot of selection goes on insiders

to make the thing because natural selection selects for the fittest and the fittest is the one that can live best in the human host. There's one very old just-so's story in this domain if you read many medical and scientific texts people have argued that pathogens must evolve to be less harmful to their hosts because why should you kill your environment?

But in fact that's wrong in my view because in essence the pathogen evolves under natural selection for its own fitness. And if that fitness is increased by being highly virulent, and we know many examples of this, then in a sense, virulence will increase once it's entered the human race. But there are multiple evolutionary pathways possible. There's no one pathway.

Increased virulence is one, reduced violence is another. So it's quite unpredictable, and Steve made the point that evolution is chance. and if you think about a new influenza strain, it requires a most extraordinary event to occur. It requires a virus from a bird and perhaps a virus from a human to infect a single cell in the human body at the same time

so that their genetic codes get jumbled and a new virus comes out. And clearly the probability of that event is very difficult to predict, it's a very rare event. And so it's always scientifically in our near term going to be a lot of chance events that we don't understand. There's an interesting spin on that in HIV. Now, HIV is in fact not particularly infectious

by the normal sexual route. Most women who are infected by their male partners just have one single particle that gets into their bloodstream out of the billions which may have entered the appropriate part of the body. But now, of course, we very stupidly have circumvented that. For example, drug users who inject blood, they're injecting blood from different, injecting from

dirty needles from different people, they're mixing up different strains of HIV in their own body. And what's happening is that some infected people, and there's a great centre here in London which studies just this, some infected people have a dozen or more distinct clones of HIV in their bodies, which then go through this

sexual process in their own bodies and produce new and super-violent strains. So these very rare events, by our own foolishness are becoming much more common. There are things called friendly microbes, just a little light relief for a moment, Mark. Can you just lighten the tone before we go for the doom? Well, the point's been made that most of the microorganisms out there are completely harmless to us,

and many of them are actually beneficial to us. All of us carry around more bacterial cells than we do proper human cells, if you like. And they do all sorts of good things for us. They're involved in priming our immune system, getting our gut working properly. they provide us with nutrients. So a portion of the calories you get from your diet will have been through bacteria before they get to you. There's actually some work recently done

showing that actually things like obesity might be influenced by these bacteria or the converse of obesity being lean depends on the kind of bacteria you're carrying in your gut. The bacteria that you carry normally, also they act like a kind of ground coverage plant, if you like, they prevent the weeds, the pathogens, from getting in. And that's why if we give antibiotics to people,

we sometimes make them more susceptible to infections with other organisms. If I may summarize, we're near the end now, it's been, as it were, a battle. I think Roy Anderson made that point very firmly. We are a battleground. And you spoke about the inevitability of new diseases coming up in the rest of this century. Where do you think we are, the three of you, at the moment, just I suppose it's a...

almost a stab in the dark, but from us very, it's much more than a stab in the dark, it's a stab, but at least in the dawn. Can we talk about, for you? Well, I'm not a pessimist, although I feel that we see, we will see many, many new events in the past few decades of witness,

you know, SARS, HIV, and new influenza strains, modern medicine is a very powerful tool, and we're beginning to understand how the human immune system works effectively. We're beginning to understand how to develop drugs against viruses, in particular. These are antiviral agents.

Our struggle at the moment has been to generate drugs and vaccines against these hyper-variable organisms such as HIV, but I'm confident over time these problems will be solved. Except again and again we've been told it comes out of the blue and you don't know when it's going to hit you. Exactly, but then if you take the H1N1 epidemic that we had in 2009-10, the vaccine from the epidemic emerging to when it hit the market was six months in an emergency.

So although of course there may be a lot of mortality of something very serious emerged first, I think the world's biomedical and scientific community would strive to find a solution very quickly. I once saw a bumper sticker in the States which said, if you think education is expensive, try ignorance. And I think that's where we're actually succeeding. If you look at HIV, there's been massive medical research.

We know a huge amount about it. But what is saving us? It is knowledge in the homosexual community in the United States, for example. there was a dramatic shift in behaviour as soon as people realised what happened. Take malaria, which we haven't talked about but that's the big killer.

There's massive amounts of money spent on malaria vaccines. But education has done a great deal in Africa, for example, and in Europe indeed, to drain swamps and the like, which allows us to avoid the infection. So I'm optimistic for a different reason.

I think after this programme I have to chat with Steve about which theory was more important, the theory of evolution or germ theory of infection in terms of its influence on our understanding of the world and our ability to change it. But the germ theory of infection, we now understand how these things happen.

We have interventions, public health, good sewage. We define civilisation as a distance between a man and his feces. We know the importance of hand hygiene, vaccines, antibiotics, all of these things. We can't unthink that now. We're ready to take these things on. And there's been tremendous progress with many infections. smallpox has gone but guinea worm is going soon so we are going to win well thank you very much

a little glimmer of optimism at the end of that thank you mark palin steve jones and sir roy and this next week we'll be talking about john wickliff and the lullards in the 14th century thank you for listening we hope you've enjoyed this radio four podcast you can find hundreds of other programs about history science and philosophy at bbc.c.c.c.c.c.org. forward slash radio four.