What was bubonic plague?

22 June 2015

Interview with

Dr Luke Bedford, Addenbrooke's hospital, and Prof. Julian Parkhill, Sanger Institute

Thanks to scientific and archaeological investigations, we now know that the Great Plague, or Black Death, was probably caused by a bacterium called Yersinia pestis. Plague infected rat flea by Michael WunderliIt spread through flea bites, and also, possibly by people coughing and sneezing on each other. Later, Ginny Smith investigates how far a sneeze can spread germs, but first, we wanted to find out more about the bacteria that cause the plague. We were joined by Luke Bedford, a clinical microbiologist at Addenbrooke's hospital, and Julian Parkhill who works at the Sanger Institute, also in Cambridge, who started by telling Chris Smith how you go about studying such an ancient outbreak...

Julian - We heard earlier that you often put plague victims into plague pits. We can recognise plague pits as large assemblage of corpses in the right time and we can carbon date those corpses and work out when they died. We can then extract the DNA from those bodies or from those bones, and identify the plague DNA inside them. 

Chris - So, these bodies are still in London in big numbers and can be excavated.

Julian - Yes, definitely. We saw recently with the Crossrail excavations that they came across a large plague pit with large numbers of bodies from the plague. So, they're underneath us all the time, yes.

Chris - What sorts of tissues do you take from those bodies in order to get DNA from them because there's not much left? I mean, they're just skeletons, aren't they?

Julian - Actually, the best place to get plague DNA is from inside teeth. The pulp of the teeth is where the blood collects and plague grows to very, very large numbers in the blood. so, there's some plague DNA left inside the teeth and it's kept protected from the rest of the soil and it's possible to get the DNA out from the inside of the teeth.

Chris - So, archaeologists come along - well, Crossrail come along, they dig up some bodies. Archaeologists come along, they get some bits of those bodies, they get teeth, they drill holes in them rather like the dentist, and get DNA from the person plus the bug that they died from. That's your interpretation, is it? The bug they died from is in there and you can then extract the DNA to study it.

Julian - Yeah. The bug they died from is in there, but there's also an enormous amount of other DNA - bits and bits of their DNA, bits of soil bacteria, mostly modern soil bacteria. So you have to know what you're looking for and you have to go and fish it out. If you know from modern sequences, from modern DNA, what plague DNA looks like, you can go pull out those bits of DNA directly from the mixture that's in that tooth.

Chris - So, that's how you did it. You had an idea that this could've been Yersinia pestis -this bacterium that could've been linked to the plague. And you said, "Well, if that was the cause then the genetic signature Yersinia pestis might be in the DNA extracted from these teeth and hey presto! You go looking and it's there."

Julian - Yes, so this was the first time a group in Germany - not actually the Sanger, but that's exactly what they did. They said, "We believe that this may have been caused by Yersinia pestis. These are victims of the plague. Can we go and find Yersinia pestis DNA in there?" And they did, yes.

Chris - Now, we actually have an idea that it really was Yersinia pestis - the bacterium - that caused the plague. Let's find out from Luke what this bug actually is. So, paint a picture of Yersinia for us.

Luke - Yersinia pestis is a single-celled organism, a bacterium. Primarily, they live in fleas, and rodents. And that's how they spread around in the wild, so to speak. And they do that by taking blood meals from rodents, and other mammals, and then when they take another blood meal, they regurgitate. The bacteria actually makes them regurgitate - through a set of genes that it's got - over into the wounds that they've just created, and that's how you tend to get it spread from person to person, it can do, and from animal to person and from animal to animal with the reservoirs in the wild. From there, it can travel and start to cause disease. Once it gets inside the body, it starts to develop, it changes the proteins that it makes and becomes resistant, to a certain extent, to the body's mechanisms of fighting off the phagocytes and other immune cells. It then travels to lymph nodes, and this is where we see the clinical picture of bubonic plague from. So, you get these massive and large painful tender lymph nodes in the groin...

Chris - These are your glands, aren't they?

Luke - Yeah. When you feel your glands raised, it's because you might have a bit of an infection. But when you've got bubonic plague, they're huge, they're painful and they're very nasty.

Chris - Is that because the bug has gone from the bite? It's replicating, or growing, at the wound site and then it's spreading through the body to those glands or lymph nodes and then causing them to swell up. Is that the reason?

Luke - Absolutely. They sort of hitch a ride, so to speak, in the immune cells of the body and gets carried and concentrated in those lymph nodes.

Chris - So, the immune system sort of helps it around the body.

Luke - Yeah. The Yersinia pestis bacteria have got a way of protecting themselves from the immune system of the body, from these phagocytes, that ingest them. From there, they have a capacity to then be carried into these lymph nodes where they can multiply and from then on, spread through the blood into other parts of the body as well.

Chris - Once you've got that condition, is it "curtains" for you? I mean, what happens? How does it make the person ill?

Luke - It makes the person ill by doing a few things. In the blood, it produces all sorts of proteins and enzymes and what it can do is make your blood very thick and coaguable. And what happens is when that affects the distal parts of your body, your fingers and toes, the small arteries in there, you get gangrene, which is where we get some of the terminology...

Chris - Black Death - yeah, because these bits are going to go black and drop off, aren't they?

Luke - That's septicaemic plague, and the other type of course is pneumonic plague, which is what we imagine with these coughing, sort of pestilent plague victims who were wandering around. And that is very bad news as well.

Chris - So, that's the plague in your lungs and you can cough it out. You don't need a flea. You can cough it out and if I cough on Julian, he's going to catch it...?

Luke - Yeah. It's much less likely to - at least there's a lot less cases - particularly these days, of primary pneumonic plague which is where it spreads like that, but it does happen.

Chris - Does that mean then that once you've got your fleas giving some people plague then people can give it to each other via that aerosol route? So, it can start off as that bubonic plague, from a flea bite, but then other cases can occur with the spread via the respiratory route?

Luke - Yeah, absolutely. so, that can be another mechanism by where it spreads. I guess perhaps in older times, you would get more - because there were so many fleas about, you would still get a lot of transmission. But these days, with less of a flea population in people, we assume, depending what the population is of course, you're going to get more pneumonic spread.

Chris - Can it be treated?

Luke - Yes. There's many effective antibiotics available and actually, if you catch bubonic plague now, you've got a pretty good chance of surviving. Around about 10 per cent of people who have plague these days - we think - die. But obviously, case ascertainment - where you have most of the plague - is sometimes quite difficult.

Chris - How many cases are there today?

Luke - In the UK, there's none. We haven't had any cases I believe since the 1930s in the UK. You still do get cases in the west of America for example and sub-Saharan Africa. But generally, we're talking about a couple of thousand a year I believe.

Chris - So, nothing on the scale of what happened in the 1600s during the Black Death?

Luke - No.

Chris - So Julian, what can you tell us about your genetic investigations then? What did you find when you studied the DNA of the plague victims that you've said they had Yersinia there? Is it the same bug that Luke is describing is still causing cases today?

Julian - Yes. When we first sequenced Yersinia, when we first generated the genome of Yersinia, it was actually with a modern strain rather than an ancient one. And what we were able to see was how this organism had evolved. It's a very recent organism. So, we're talking about the plague in the 1600s, but plague probably evolved only a few thousand years ago. And it used to be an organism called Yersinia pseudotuberculosis. Yersinia pseudotuberculosis causes enteritis, a kind of diarrhoeal disease in humans. It's a mild disease and it also causes a diarrhoeal disease in fleas. So, it infects mammals like rodents and it infects fleas.

Chris - The mind boggles with the prospect of a flea with diarrhoea! But do go on.

Julian - A very careful experiment I think you have to do there. So, what Yersinia pestis did was it found a way to jump, to change from going through a faecal-oral-diarrhoeal route in fleas and a faecal-oral-diarrhoeal route in mammals. To suddenly connect the two it only required one or two extra genes to do that. And if you look in the genome, if you look at all the genes it's got, then it's got all the genes that it needs to cause the disease we know about now. It's still got all the genes in there that it used to use to cause diarrhoea in humans. And they're still all there. They're just knocked out. They're inactivated. So, by looking at the genome, you can understand how it evolved, where it came from, and how it changed.

Chris - Can you answer the big question which is probably the crucial one though which is, if it's so similar today to the strain that was causing the Black Death, why did so many people die in the 1600s, yet today, it's only a handful?

Julian - No. Unfortunately, we can't answer that question. We can study very large numbers of plague organisms now and we can look at the diversity of plague and we can use that to reconstruct where it comes from and it's very clear that plague is endemic and it's common in China. It circulates in rodents and around there in China. And it has come out of China and caused at least three plagues: The Justinian plague before, the one we're talking about, the Black Death, and then another plague in the 19th century. So it's continuously evolving in China and it's come out of China multiple times to cause pandemics. Now, because of the way that the ancient DNA was sequenced - because the people who did that took what we know about plague now and used to fish out what was there - we can't say that there wasn't anything new, anything we don't know about. We can find out what we know about. We can't say there isn't anything in that genome in the ancient plague that we didn't know about. But it looks very much like it's the same organism causing the same disease.

Chris - So, there might still be something else that was in circulation at the same time. We'll just have to wait and see I suppose. Julian Parkhill from the Sanger Institute and Luke Bedford from Addenbrooke's Hospital, thank you both very much.

Ginny - One theory is that the Black Death in 1665 spread so rapidly because this pneumonic version became more prevalent. And as you've probably experienced with colds and flu, and that sort of thing, things that spread by coughs and sneezes spread very quickly and very easily through homes and through schools. And that's because when you sneeze, the amount of virus or bacteria that's coming out of you is huge and it can go quite a distance. So, I've got a slightly, well hopefully, not too disgusting because I'm not actually going to be sneezing. Well, what we're going to do now is recreate some sneezes using this spray bottle and look at how you might be able to stop them spreading. So, I'm going to someone to come up and do the sneezing for me. Who wants to do that? What's your name?

Peo - Peo.

Ginny - Peo, great! If you just hold that bottle for me. What I'm going to do is I'm going to put a big sheet of paper out on the floor. Don't squeeze it yet and not when it's pointed at me, okay. Okay, so I've got a big sheet of paper here on the floor. If you sort of crouch down for me and put the bottle right at the edge of the paper and then when I say go, I want you to give it one nice big squeeze and we'll see how far the droplets go. Okay, ready? 3, 2, 1, go! Can you see the droplets on the paper?

Peo - Yes.

Ginny - So, how far have they gone?

Peo - Almost all the way to the end. In fact, you can see a tiny drop just at the end.

Ginny - Okay, so we've got about a metre and a bit of paper there and the droplets have gone quite a long way. What's interesting is you can also see that there are some big droplets and there are some really tiny little droplets. And that's the same with the real sneeze. They're the kind of big globules of spit and snot that come out that you might be able to see. But you're actually spraying out tons of tiny weeny particles and there was some research that came out a little while ago that actually said that we used to think they could go maybe a few metres. But these tiny little particles can actually get picked up by air currents and go a lot further, 200 times further than we previously thought. And that's far enough to infect everyone in this room definitely. So, what can you do when you sneeze to try and stop yourself from infecting other people?

Peo - You cover your nose.

Ginny - You can cover your nose and mouth, exactly. So, that's what we're going to try next. We've turned the paper over so we've got a clean side and we're going to try covering it with my hand. So, that's what a lot of people do when they sneeze, isn't it? You put your hand in front of your mouth. So, I'm going to put my hand. Where do you put it? Kind of a few centimetres in front of your nose and then I'm going to countdown again and I want you to spray. Do you think I'm going to block all of it or do you think we'll see some of it on the paper?

Peo - I think we'll see some.

Ginny - Let's have a look, shall we? Here we go, 3, 2,1, go! There's a lot of purple die on my hand so I did manage to block quite a lot of it. What can you see on the paper?

Peo - There are a few tiny droplets in the middle of paper. At least it didn't reach the end this time.

Ginny - That's true. So, it's better, isn't it? A lot of the big droplets, I've caught. But if you look closely, there's actually quite a lot of the tiny weeny little droplets that have got through. And also, now have a think about what's on my hand. What am I going to do now? When you've sneezed, do you always go and wash your hands straight away or do you sometimes pick up a pen or go and shake hands with someone? Would you want to shake hands with me after that? No.

Female - My mummy always says that if we sneeze or cough by our elbow then we won't put it on our hand and it's less likely to spread.

Ginny - Exactly because how often do you pick up a pen with your elbow? Not very often.so actually, that is now what people suggest that you sneeze into the sort of crook of your elbow, the inside of your arm. What that'll do is it'll make it less likely that you pass on the disease. The other thing you can do is you can use a tissue. A tissue is a bit bigger than your hand. So, we're going to try that now, last try and I've got another clean sheet of paper. This time, we're going to put the tissue right in front of the spray bottle and see what that does. Ready, Peo? 3, 2, 1. How's my paper looking?

Peo - Completely white and the tissue is looking very purple.

Ginny - There's a big gross purple splodge on the tissue but I can see - there's one tiny weeny drop there, but I think that's it. So, tissues are great because now, what I can do is just ball that up, chuck it in the bin and the infection is gone. If you don't have a tissue, the crook of your arm is the next best thing because really, you don't want to be sneezing on your hand because you use your hands a lot. But this just shows quite how fast sneezes can spread. It's not really surprising that if you had lots of people living in cramped conditions sneezing on each other, it didn't go well.

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