SoHP: Johannes Krause 2/16/17

welcome folks thank you so much for coming this evening to the third in our series of talks about what's new in the fall of the Roman Empire a lot sponsored by the initiative for the size of the human past with the support of the department of classics and the department of history here at Harvard the initiative our initiative our thing would like to work oh this is getting interesting what's new in the fall Roman Empire yay the initiative of the science initiative for the science of the human past at Harvard and aims to bring together the power of the advanced sciences and the questions and inspirations of the humanities and the social sciences to illuminate the human past in all its splendor first complexity in which our present is so deeply embedded tonight is a very very special occasion that you've happened on mostly unwittingly in the life of our initiative for this presentation marks the first public beginning of an exciting and amazing new transatlantic collaboration a joint venture of the soh P the initiative for the science of the human past with the new Max Planck Institute for the science of human history in llena whose founding director professor johannes causa will be speaking to us this evening our new research program here and there will be called on both sides of the Atlantic the Max Planck Harvard Research Center for the RPO science of the ancient Mediterranean which I suspect will pronounce as M ham now if that name sounds like a bunch like it might have come out of a committee I can tell you that it did come out of a committee and the long month very long track tations of the Office of General Counsel of Harvard University and that is the Max Planck Society Munich anyhow it's working it's great this is the beginning our two previous talks in this series were brought to us by Kyle Harper at the in October who memorably addressed questions of infectious disease and ecology nature did it was his in some summary answer to the fall of the Roman Empire and another talk in December on new ways of studying the Father Roman Empire in the 21st century tonight we're going to zoom out timewise and zoom in focus wise with the talk by a remarkable scientist one would be tempted to call him a rising star if it were not true that his star has already risen swiftly and spectacularly Johannes causa has been doing amazing things in very short order and those amazing things are contributing in a very important way to the questions that historians and archaeologists are wrestling with right now about the fall of the Roman Empire starting with this question did mass death mass death from disease not the wheels of the Roman Empire's economy and usher in a final collapse of the Roman imperial system that had dominated the Mediterranean its civilization its economy its geopolitics for some seven hundred years by the time of the reign of the Emperor Justinian in the 500s although some have controverted this new evidence is fast accumulating beyond the written sources we have long known for instance about the nearly quarter of a million deaths recorded in the imperial capital at the first outbreak before the Imperial accountants gave up counting in despair the new evidence is deepening and changing our understanding of the terrible pandemic that struck the Mediterranean and beyond in awful and successive waves from 541 to about 750 ad archaeological evidence is piling in the form of mass graves recently inventoried and mapped biomolecular evidence is piling up also in the form of the robust identification from ancient DNA of the pathogen itself there is now no doubt that the new disease the main killer that stunned the late Roman Empire in the 500s and subsequently was your Sania pestis bubonic plague now also identified as the pathogen behind the medieval Black Death in this astonishing voyage biomolecular discovery of ancient pathogens and of their evolutionary and epidemiological trajectories professor Khalsa and his group have played a truly leading role as a child growing up in Thuringia then for a still still a few more years in East Germany the young Johannes as he has told me always loved history but that did not seem like such a smart career option in those years unlike today and he became a biologist he later earned his PhD at the University of Leipzig and worked extensively with Vontae table at the Max Planck Institute for evolutionary epidemiology if you meet evolutionary anthropology also in life station then he began a particularly Swift rise that had him go from assistant professor to full professor of scientific archaeology at Tubingen where we first met right in the lab where DNA was first identified in the 19th century and then in another instant it seems to me he became the founding director of this magnificent new Max Planck Institute for the science of human history in llena which is bringing unmatched resources and amazing talent and intellect to exactly the same task that science of the human past has been pursuing here at Harvard at a more sedate rhythm in its present form since 2011 from professor Krauss is long-standing and fruitful collaboration with David Wright in his lab and from our own friendship and collaboration has emerged the Max Planck Harvard Research Center for the Arceus the ancient Mediterranean M Han my own group of graduate students has profited immensely from their collaboration with professor Krause's group and his students in combining the historical written evidence the fill illogical analysis of the Greek Latin Arabic Syriac texts and the archaeological and biomolecular archaeological evidence genomic evidence for reconstructing the course and nature of the various waves of ionic pandemic at the end of antiquity Johannes has made wonderful contributions to our kitchen etics it would take me all night to go through them in detail from the question of the Fox Pro gene among the and ourselves to identifying the pathogen something dear to Bostonians the pathogen or not so dear behind the Irish potato blight and famine about our subject tonight professor Krauss this group made a fundable fundamental contribution with that of Hendrick Pine Point our when they were able to reconstruct a draft genome of the bacterium of the Black Death in 2011 since then professor Krauss has made a series of signal contributions including reconstructing the details of the bubonic plague genomes that struck Mach say early in the 18th century most recently he has recovered his group has recovered a high coverage Yersinia pestis genome from a sixth century Justinian ik plague victim in Bavaria only the second site to yield robustly authenticated evidence of the Justinian ik pandemics pathogen we are now in other words entering a new biomedical and archaeological world in which collaborative ventures are illuminating the deep evolutionary history of disease in exquisite detail changing our understanding of the nature extent impact and course of ancient and modern pandemics with abundant lessons for specialists of modern infectious diseases as well as for archaeologists and historians tonight professor Klaus ax will take us on a remarkable tour of the long delay of the terrible disease of your senior pestis which to our astonishment we learned only a year ago already existed in the Stone Age he will follow that story down to the form that struck France in the 1720s and to spur our thoughts and discussion in the time that will follow we will have the privilege of hearing brief comments on the talk from the historical perspective from professor Kyle Harper of the University of Oklahoma and from the microbiological perspective from Tom Benjamin member of the steering committee of the science of the human past and with whom both I and professor Harper got our first experience with ancient DNA trying to identify that of your senior pestis in vain in his lab in the department then of pathology at the Harvard Medical School but with no further ado please join me in welcoming Johannes causa of the Max Planck Institute for the science of human history and of M ham who will speak to us tonight on the genetic history of plague from the Stone Age to the 18th century via the Roman Empire Johannes welcome this isn't what's insane meeting flies [Applause] okay okay remote control doesn't work but yep so first of all thank you Mike very much for the invitation and a pleasure to be here talk today about some of the research that my group has been focusing on over the last few years and trying to uncover the genetic history of a senior pestis and it has actually brought us from the medieval time down to the Roman Empire and now even into the Stone Age and I hope I can take you on that voyage also tonight and it's also my pleasure to be here and kind of starting this initiative that mike has already mentioned in his presentation this new a Max Planck Research Center together with Harvard and the Max Planck Institute Indiana which I'm very excited about which I would probably pronounce mom and not M ham but I'm certainly open to any kind of suggestion on English pronunciation so like I mentioned before this is really a voyage that has brought us into many different time periods now the Roman Empire is just one slide small chapter I would say I think most of it is probably in the medieval time of what we know certainly about the genetic history of the play currently but as I said and as Mike already mentioned it even brings us now into the Stone Age the history of most infectious diseases that we find in the human population today actually starts probably even earlier and probably sometime in the so-called and Neolithic noticing that the presentation is again a bit smaller yes we have actually found how to make it bigger so I will try that now okay now that doesn't really work so let's keep it Oh doesn't look good I just see the pizza of death that's a little bit but it's Claire's okay then the writing is a bit M now I can already see on the next slide that has completely jumbled their ex still I better leave it a bit smaller so people I don't see in the back should come into the front a wonderful red couch here looks like sequin Freud space um yeah it's worked better so it is really a story that probably started already pretty early on in human history some people suggest that it was sometime in the early Neolithic so the time periods when human became sedentary farmers aquaculture lists they started to live in much denser quarters together and actually provided them very good conditions for pathogens to spread it is also hypothesized that many of the pathogens that we see within the human population today were actually transmission from our domestic animals that were domesticated during the time so called zoonotic transmission and because we find the closest relative of those human diseases such as measles smallpox flu tuberculosis play leprosy pertussis actually today in our and domestic animals so this is why it's thought that many of them actually entered the human population from those animals that can be domestic animals but also commensals that live in close proximity to humans such as for example mice rats and then of course when human populations became even bigger civilization started some of those pathogens then caused major outbreaks that we then also know from historical records Sam I mentioned here like the plague of Athens and to destruct the Roman empires of the Antonine plague and the dynamic plague and then of course the famous Black Death this major pandemic that happened in the 14th century which is probably something that most people are quite familiar with but was very unclear from the historical records however was what pathogens were actually responsible for those large outbreaks in the past I put some question marks on the smallpox or measles for plague of Athens Antonine plague but for the two later one suggests in any place in the Black Death I will actually show you we have no very strong and molecular evidence as Mike already mentioned that those have probably been caused by a senior pesos of bubonic plague dude for many people if you kind of hear both plague and smallpox that sounds more like something from the past something that is actually not so relevant maybe to us today it is relevant for historians it's relevant to understand what happened in the past but it might actually not be so relevant say for medical research for example and in fact if we go back to a 6070 years there was quite a lot of medical researchers that said even infectious diseases are not so interesting anymore to be researched because we have vaccination programs and because we have antibiotics so that by the end of the 20th century people actually suggest that there will be no infectious diseases anymore because of this amazing kind of new medical treatments that we had but of course we know today that this unfortunately did not happen in fact there's only a single pathogen that has been more or less radically that is smallpox even though it's not completely eradicated because there's still smoke two laps in the world one in Atlanta and one in Novosibirsk that still basically have this pathogen in case somebody might use it as a bio weapon and they could still do research on it but what we also see is that since the 1980s we see an increasing amount of new pathogens emerging from different parts of the world of course everybody has seen and heard much about HIV but also SARS hunted the Ebola outbreak from only two years ago in western Africa or all examples of pathogens that are spreading in the world today so infectious diseases are still very much topic in medical research and the other problem we have is reimbursing infectious diseases some of them by antibiotic-resistant like for example tuberculosis which is actually spreading in the world today again causing thousands in even in case of tuberculosis a hundred thousands of casualties every year so this is a very very hot topic of research however there's actually very little that we know about the early evolution of pathogens and that is mostly due to the fact that if you want to study evolution in most cases people have fossils to look at so I've been working a lot in the past with Neanderthals and also working with mammoths and cave bears and all kind of megafauna and for all of them we had a pretty good understanding already about their evolution because we can actually look at bones fossils from the past we could actually understand how they changed and through time however for pathogens we often of course do not have that we don't have fossilized bacteria even if we have them they're just a round shape but they don't really tell as much about the biology of that round shape that could be any term other type of bacteria that we are looking at there so therefore we know very little about the early evolution of the pathogens about evolutionary rates so how fast do pathogens change over time what's the mutation rate over hundreds of thousands of years and also we know very little about host pathogen interaction so how do the pathogens change to become human pathogens but also how do humans react through time to the pathogen are there actually genetic changes in the human population for example resistancy genes that are spreading within the population that is something that has really not been much investigated and understood and this is basically what we noticed about five six years ago and that there's really a lack of information from the past to study ancient pathogens and this is when we studied and started this new field that we now call ancient pathogen genomics which is basically researching directly ancient pathogens by taking skeletons from the past and we distracting the genome of the pathogens that might still be left behind in those ancient skeletal remains for example taking teeth taking bones taking mummified tissue from the past and extracting DNA from that to be then able to tell something about the evolution of those pathogens so that basically provides some sort of molecular fossil record we don't get kind of fossils in the kind of form of some sort of shape or bone but we better get the molecular fossil in genome that we can then analyze and compared to modern pathogen genomes learn more about mutation rates through time your own sample about this host pathogen interaction and of course we can also provide historians provide archaeologists with this important information of what actually caused those billions of casualties in the past so that just in the ending page the plaque death the Antonine plague and so forth so what pathogen was actually responsible for those large pandemics in the past and we've done quite a number of research projects together with my now three group leaders and back-in-the-day postdocs and PhD students Kirstie boss I kinda have a conclusion a Schuneman and the first where we started with the Black Death for something I will also focus today a bit about but we also looked at ancient leprosy so we were actually able to reconstruct leprosy genomes from medieval and now also early medieval time as Mike already mentioned we've also been able to reconstruct the causative agent of the Irish potato famine which is actually not a human pathogen with the plant pathogen that affect potatoes and at the time and we've also looked at micro bacterium tuberculosis in fact from the new world pre Columbus which was very exciting because people thought it was actually not their pre Columbus we could show it was there but it was not a human form of tuberculosis but in fact a sealed tuberculosis which was very exciting so some zoonotic form that was transmitted from seals and into human populations and then recently we worked on the stomach contact of this fellow here which is the Iceman he let's see an ice mummy that was preserved in the out for more than five thousand years and we could actually reconstruct from the stomach content in your back to pylori so bacteria that live in the stomach that can cause ulcer that can cause also stomach cancer and was quite interesting to compare this five thousand-year-old bacteria to modern bacteria and see how they change to the last few thousand years but then today my main focus is really plague so what we know about plague and today is that your senior pastors is usually not found in human populations it's actually not a human pathogen per se if it is found in human populations usually some sort of accident really is found in wild rodent populations such as squirrels Journal's marmots and eventually it can get transmitted from those wild rodent populations into commensal rodent populations that live in close proximity to humans for example rats or mice and the transmission happens actually by fleas the fleas can abide infected individuals and they take the bacteria up in their stomach what happens in the stomach of the flea is actually that those bacteria they built a biofilm that clocks the stomach of the flea so the freaking actually not swallow the blood well then actually happens the flea is actually starving and it keeps on biting and every time it bites it actually kind of inject bacteria into the business individual but then happens to rats and mice is that they actually also get bubonic plague and they die and if they're dead the fleas look for the next warm body and if that is not read or mice by the human and actually humans can get infected and that can cause bubonic plague so the bacteria kind of migrate to the next lymphatic node and we're close by they get swollen but you replicate here you get this Bubo which you think is the name bubonic plague and then the bacteria basically replicate they move into the body and if you don't get antibiotic treatment in about 50% of all cases after seven to ten days it costs death actually causes multiple organ failure you have necrotic tissues who hands and feet often get necrotic that turn black this is the name black death came from and it quite it's quite high mortality 50% that is comparable for example to Ebola this is actually not the only form how people can get infected there's also a form where humans can infect other humans not by direct flea transmission but actually by oral and droplet infection the humans can get infected and the bacteria move through the body and then in fact the whole basically body they eventually also in fact the lungs if you have an infected landing you cuff up bacteria somebody else inhales the bacteria you can get something that we call pneumonic plague which is actually a very severe form of plague because when you see the first symptoms which is usually after 15 to 20 hours you only have about five to ten hours to live because it's very very fast so mortality is still today very high if you get infected directly into the lung and antibiotic treatments usually too late because the symptoms arise so late and within 24 to 48 hours people actually die in there has been actually even a few cases where people that infected in the lab for example by inhaling the bacteria so in the Grand Canyon in case a couple of years ago with somebody was dissecting a mountain lion and above leader died of the plague itself the mountain lion and during the dissection properly inhale the bacteria and the next day the person was dead so that's pretty bad so the senior pesos is still found in the world today there's actually many places in the world that's found most common it is found in South Asia and East Asia but there's also some reservoir population in Madagascar where there's outbreaks every couple of years and then also in the United States especially and the western part of the United States there are reservoir population mostly squirrels or groundhogs they actually carry the bacteria and again there's a few dozen cases in the US and a few thousand cases worldwide where people can or get infected from the bacteria at pony-play or some pneumonic plague form a doozy mortality today is quite high because people know how to treat it there's a number of antibiotics that can actually be used for treatment and they are actually quite efficient but if you don't do basically any antibiotic treatment and mortality of course is still very high so the pathogen acceptance whatever as its virulence it hasn't really lost it through time so if you then look back into the past trying to understand ancient pandemics and trying to see which ones might have been caused by the plague and the first one that was already mentioned by Mike where people have suggested based on historical records and this case was procopius who basically reported the historical text about this outbreak that we now call the Justine Yannick plague which started in the mid-60s done the very good reports that she actually gave about this disease people suspected that it might have been caused by the just by by a senior pastors so what's a plague pandemic this is also why it was called and already and some years ago the first plague pandemic even though no well actually our evidence was available by the historical records really suggest that the Ksenia pestis caused this outbreak the second pandemic then the people thought was probably related to your senior pesos outbreak was the black death which happened in the mid 14th century it was a very short time period of only about five years it is thought today that about fifty percent of the European population died in this major pandemic and then stayed on in Europe there then multiple outbreaks in the next 350 years it happened again again in waves it's about eighteen to twenty waves of plague where I will talk later about if they have actually been independent wave weather was the same pathogen that course and then the last big pandemic that we think was caused by Yersinia pestis and was in the nineteenth century it actually started in the United province in china in mid nineteenth century and some people say it's still ongoing other people say it kind of disappeared the most antibiotics in the mid 20 century but it was basically around for about a hundred years and again it killed millions of people especially in East Asia but through the harbor's of Hong Kong it then also disseminated the disease all over the world so the fact that we have it in the western part of the United States today that we have a de Madagascar in central Africa is probably due to this event here that basically by the ship traffic by the clovelly globalized world and the pathogen actually spread by ship traffic all over the world so what we have been been interested in when we start this work is trying to see and trying to identify which of those large outbreaks were actually caused by the pathogen because when we started this work there was a big debate among historians whether especially those ancient historical pandemics were caused by Yersinia pestis or whether they might have been actually caused by some other pathogen in fact some people suggested especially for the Black Death there was some virus some hemorrhagic fever a pathogen that cannot be identified anymore because it's extinct and has been really a lot of debate and there's been some early molecular work that was disputed by other ones that suggested it was all contamination so it was was a really hot debate that we basically stepped into but the molecular identification of of plague is actually not so straightforward it's actually not so easy because if you have ancient skeletons and you look for molecular evidence you look for genetic material like DNA if you extract DNA from an ancient skeleton like an ancient tooth or bone you actually get a suit of DNA all kinds of DNA that is the DNA of the human itself but actually the vast majority of the DNA that you get from ancient skeletons is not even from that human it's also not the bacteria that this person carried but it's actually environmental DNA because a bone is really like a sponge it basically sucks up all the DNA from all kind of microorganisms that live in the soil you really get an environmental sample if you want but trying to identify them the pathogen from the soup of DNA is actually not very easy one possibility is what we call a shotgun approach we have this wonderful sequencing technologies today that can produce millions and even billions of DNA sequences so you can just take an ancient sample extract the DNA and sequence the hell out of it if you do that however we're stuck with a problem that now you have millions of DNA sequences that you have to try to sort to try to identify to try to know which DNA sequence actually comes from which organism in which DNA sequence actually might be for example from the ancient pathogen we have been working hard in the last few years on tools and to identify those DNA sequences so there's a few that we then called metagenomics so you take DNA from environmental samples and trying to make sense which DNA fragment comes actually from which organism and one of my group leaders in the department alex and i have ink has developed this tool that we call mold don't want to go much into detail here but with this tool actually is is an alignment tool so it takes all those DNA sequences and compares it to all genomes that have been produced in databases and that is something that people have been doing already for twenty or thirty years and with the tool it's for example cold blast but that tool is very slow but as this tool is much much faster it's several hundred fold faster than kind of the normal tool that people have been using in the past so it is so fast that we can now actually analyze one billion DNA molecules in less than 24 hours so we can really produce massive amounts of DNA sequences from this ancient sample and then just say from which organism every DNA fragment comes from which is great but again it produces a problem the problem is the output is very very difficult to read because the output basically looks like that so you see this cytogenetic tree hard to see for the people in the back I guess so baby if you take such a sample we see something like two and a half thousand different organisms DNA in such an ancient skeleton and I was very tedious to find out which one of that could actually be the passage that has been responsible for the death of that person so you can then zoom in and then you look for example in this case we have a lot of micro bacteria that cause tuberculosis but you see actually many many many different species of micro bacteria hundreds of different micro bacteria so which ones are now actually the pathogenic ones which one are not actually the ancient pathogen which one might just be from the soil so it's quite difficult what you can then do is we can look at each individual DNA fragment compare the two reference sequence here so this is a sample where we suspected that might have tuberculosis you have many many DNA reads you can actually if your comparative reference see that they have a lot of differences so every kind of colorful bar here is actually a difference to the reference you can actually see is less than ninety percent identity so this is something we would call a false positive so this is probably not TB whereas in this sample here we have a lot of reeds they are looking very very similar so more than 99 percent sequence identity in this case would say that's a true positive that's indeed tuberculosis it's not quite um easy to find and the pathogen especially if you don't know what pathogen might have been present in this ancient skeleton sometimes we in a much better situation like for example for this particular cemetery here that we have been first studying and about six years ago I mean where we got skeletons from the East Smithfield Cemetery which is in the central London and those M skeletons were excavated in the 1980s when they were building one of those beautiful cucumber like new office buildings close to the Tower of London so there's a toe of London here they found about 500 skeletons and based on historical records they knew that this was a plague Cemetery historical records actually said that it was only using the Black Death because they had so many dead people in the city of London that that term is filled into a cemetery and they closed it afterwards again so we can actually be rather sure that most of the skeletons that we have from this site died during the Black Death so now we have some idea okay that could then be senior pastors because that's something that people have been discussing was responsible for this particular outbreak George we then did is we analyzed 50 skeletons from this collection and indeed in 20 of them we could find with classical PCR yes senior pestis at this point we could have actually stopped our research at this point we could have said okay the senior pestis is present we could show it in Ephesus was present in the Black Death it was likely the causative agent of the Black Death but we actually wanted to go one step further we actually want to go one step further and reconstruct the entire genome of this bacteria to understand better how it actually changed through time what we can actually say about the genomic elements of this ancient pathogen but that is now very difficult because again if we look at the DNA that we get from the skeleton there's such a tiny fraction that is actually a senior pestis how do we get enough pieces to puzzle together an entire genome and to do that we have developed methods that we call a DNA capture where we have devices such as for example those microarrays which are small pieces of glass and on the surface of this piece of class you synthesize DNA you can for example synthesize an entire genome or Ksenia pestis of modern a senior pestis then incubate your DNA with this piece of glass the fragments that are similar to the DNA on the piece of glass will actually bind to this piece of glass and everything else that is not similar you can actually wash away but that you enrich for your senior pastors DNA you can put it in one of those wonderful sequencing machines and then reconstruct the escena pestis genome and based on those hundreds of thousands of millions of pieces and this works actually quite well if you see the amount of your senior pastors DNA with that from the skeleton before we did enrichment because it's very very low nafta enrichment was actually very very high you then still have another problem and that is the problem that if you then have that DNA on this ancient gallatin some people might still say how can you make sure that this is indeed 660 year old DNA couldn't that also be bacteria that just live in the soil today couldn't that be something that is actually modern contamination from the lab so how can you actually show that this DNA is indeed old that it's authentic ancient DNA and to do that we have developed some methods the last couple of years where we look at some specific properties of DNA when it gets old because when DNA gets old like everything it actually folds apart and actually DNA and humilate sometimes we call DNA damage and this DNA damage to chemical modifications to the DNA caused changes to the DNA sequence specifically changes where C's in the DNA become T's and that leaves a very characteristic pattern so if you look along the DNA fragment for those changes you can actually see that there's a lot of changes at the beginning of the DNA fragment and at the end of the DNA frag so busy this damage accumulates in this part of the DNA that is not so well protected like the inner part of the DNA and that is something that we see in the undertale' DNA which is 40,000 years old you see that in DNA from any kind of megafauna from the past but where we do not see that is in contamination and we don't see that in DNA from modern people or from modern DNA from the lab we could even show that it accumulates through time so this is time this is the amount of damage so the older the DNA gets the more damage accumulates so if you have for example and samples that are about 100 years old they have about 10% damage here are some that are 500 to 2,000 years old you have about 20% damage if you then look at the DNA from for example the black death time we look at the human DNA it has this typical smiley here so it has a lot of damage whereas and if you look at the Essene your path of DNA we can actually see the same pattern so therefore we can assume so we see 20% damage that this DNA is indeed it about 500 years old right that really tells this DNA must be old that cannot be modern contamination it cannot be something from the soil this is actually ancient DNA that is hundreds or even thousands of years old that basically then allows us to reconstruct really complete genomes the complete blueprint basically of this ancient bacteria from the past so in this first study we reconstruct about 99% of the genome of this ancient bacteria we have seen every position about 30 times so we have a very high quality sequence that is really comparable to modern bacterial sequences that you could produce in any microbiology lab what we can then do if we have those ancient genomes we can actually build phylogenies we can build family trees of ancient and modern bacteria and those family trees then look for example like this this is the family tree of your senior pestis this is all based on modern genomes of your senior pestis if you put them all together those modern genomes mostly coming from rodents not from humans you see that there is this four major branches which we call branch 1 2 3 4 where 80% of all modern a senior pest is Fault in then you have some that kind of fall basal to those ones here which are called branch 0 and the most recent common ancestor and all those genomes have about 5000 years ago which we were able to calculate using the ancient genomes as you will see the closest relative is actually soil bacterium that's something that is pathogenic to people but it's not getting transmitted by fleas if you would get it into your blood it would still kill you but it cannot be transmitted by fleas when we then take this family tree of modern your senior pestis we can then take our ancient genomes and stick them into this family tree to see how the ancient ones are related to the modern ones to tell us something about what might have happened in the past and how modern and ancient ones are related when we do that for the Black Death but this ancient genome that we reconstructed from the London site we can actually see it falls right here in this position very close the most recent common ancestor of all those different branches here which 80% of all the modern trains fall into that was actually very exciting to us when we saw it the first time because you can actually already imagine if you just look at the family tree without having this ancient London strain here that something has happened here because you have all those strains diverging like a star from each other that's usually the sign of a pandemic or some major event to basically see that the population size of this bacterium is increasing a lot so it's basically spreading within the population that we seem to pick up here there's also very exciting for us to see that it basically falls very close to this position here so that the Black Death strain seems to be close to this event where the bacteria are spreading which makes a lot of sense because the Black Death is a major pandemic so this is probably also then seen in this tree here but then that was not enough to ask because we still wanted to understand more about what actually happened after the Black Death in doing the Black Death because there were many different hypotheses that people have put out and on this ancient pandemic and one hypothesis was whether there were multiple introductions of plague into Europe and that is true for the Justinian ik plague that is also true for the Black Death because we have different strains we have different events we have 20 different outbreaks after the Black Death in Europe was it every time brought into Europe again by people traders ships any kind of contact with central asia or eastern asia or was it actually that there was some sort of reservoir population was they actually a rodent population in europe that carried the bacteria and gave the bacteria again again into the human population and what we also wanted to look at is whether the bacteria actually traveled all the way back to Asia because if you actually paid attention in the three you could actually see that it was on a branch back here leading towards this branch one which was actually the branch that calls to Hong Kong plague in the nineteenth century so we wanted to also ask that question whether the bacteria actually might have traveled back all the way into Asia to address those we have in the last couple of years looked at many different outbreaks many different epidemics mass burials that we had from Barcelona from Eastern Europe and Russia here from Germany and from a market place in southern Germany where when they did a parking lot they actually found 150 skeletons in the middle of town that all died during a very short episode probably within a week or two weeks in a town that had 3,000 people at the time so basically a mass burial as mike has been also researching at for the Justinian a plague and we then wanted to see how do the plague pathogens look like in all those at different contexts we also did a lot of sequencing a lot of reconstruction again of those inch pathogens if we then look again how they're related to those modern Amir senior pastors genomes here's again London from the Black Death the first one that we were actually quite excited to see that was coming from Barcelona also from the time of the Black Death actually falls in the phylogeny here have you seen if you have to see that it falls directly on the London plaque that is actually genetically identical the black death from the Mediterranean and the genome is 100% identical right which is very exciting and interesting because it tells us that this pathogen that killed those 50 million people as genetically actually not changed much in Europe at the time it was introduced in Europe it's Bratt in Europe but it didn't really change right which is quite interesting we also now have a genome from an outbreak that happened in London in 1360 and that falls under phylogeny here very close to the one from the Black Death it has three extra mutations which is also not a lot and what is quite exciting also is we have yet another genome that is actually from BullGuard City which is in Eastern Europe that falls again on this branch here we basically have like pearls on the line those ancient genomes leading towards this big branch here which caused the 19th century pandemic and that is interesting because we basically have micro evolution you have this pathogen evolving but it is all in sites in Europe and then leads towards the branch that then later on causes this big pandemic in China which suggests that actually the evolution of this pathogen happened in Europe let it indeed spread back to China if you then look at Elvan and those other sites in Europe in the kind of centuries after the Black Death they actually build their own little branch here so this is El Venkman this is several genomes from the last large outbreak in Marseilles in the 18th century in Europe and they built their own little branch here would if you want to be branch five and that is quite exciting as well because it basically tells us that there hasn't been much new introduction of plague from the Black Death because you most of the genome that we then find later in Europe and we have another doesn't now they all fall in this branch so we have many they have a European specific plague branch that tells us that the plague came to Europe I did it stayed in Europe so it was not multiple introduction but it was just around there was basically a reservoir population that was established in Europe maybe some rodent population that we don't know about because rats are not a good reservoir because they also die of it so it was we've much more likely to have some other reservoir population like in Asia where you have for example gerbils which are basically immune against the disease they can carry that it'll die of it you need something like that to have a reservoir one hundreds of years but then again what say was the last big outbreak in the 18th century then it disappears so the reservoir seems to not be present in to the for the kind of black death and aftermath we have this current model where we think that in the mid 14th century it comes somehow from Eastern Europe into Europe the kind of reservoir population gets established but you also have the micro evolution of your senior pastors and some spread back into Asia this branch one goes back into Asia and then later on in the nineteenth century spreads all around the world so that's the same strain that evolved in London in Europe that you now find for example in the Grand Canyon right all that you find a Madagascar in Africa that basically spread then in the nineteenth century all over the world basically our family tree now gets enriched by another branch by this kind of post black that's European branch and then this branch one year basically comes out of it and then spread all over the world we talked a lot about the kind of late medieval time and early modality of course I also want to talk a bit more about the Justinian ik plague which is of course a very exciting other and historical and plague pandemic Mike already did a great introduction and has actually done fantastic research and trying to identify it archaeological evidence for this plague and together we have been analyzing a number of skeletons from different sites and we have been looking very very hard I would say since the first time we talked about them to try to find skeletons with your senior pastors from mass graves from all over basically the former Roman Empire um but it was very difficult we really haven't really found too much but we're quite excited now that we actually have found some and those come from two sites in southern Germany one called open air ding one called a shrine they're very close to Munich that I guess many of you have heard about not just Oktoberfest cities and the other side is actually Valencia and which is also quite exciting because that is I'm also at least part of this kind of decomposing Roman Empire I'm at the time in the mid 6th century but we now have genome so complete your senior pastors keynote from those three different types and we can put them now into the family tree right so if you look at the family tree again and we see all those different genomes here this is the black death and this is the aftermath of the black death you would expect the just in any plague to not fall into this um kind of group here and in fact they indeed you don't do if you put them in a family tree they actually fall here on their own little branch actually at that end like a branch that hasn't left any descendents anywhere in the world all the hundreds of genomes that we now have is nothing that busy goes back to the Justinian plague I'm not quite sure why um it seems to disappear like the post black death at European branch also is a dead end it also disappears in the 18th century maybe the same has happened here this would actually speak for the fact that there was an introduction into Europe the oldest historical records we have of the Justinian plague off from Egypt we can spread through the Mediterranean was around in Europe for about 250 years but it probably then disappeared and indeed between 750 in the mid 14th century there seems to be no evidence no historical evidence is so far for a major outbreak of the plague again so it seems to have disappeared again why is not clear and some evidence suggests that again we had an establishment of a reservoir population so there was some rodent in Europe where the bacteria were basically thriving in but again we don't know exactly which rodent population that was and of course there's also earlier plague outbreaks I mentioned the plague of Athens the Antonine plague in the Roman Empire as well where began galleon early historian has actually told us a lot about the disease we seem to kind of suggest maybe it's smallpox um some people also suggest with measles other people say with the plague is kind of unclear we have also been looking hard for finding evidence for your senior pastors in victims from as earlier outbreaks so far we haven't found anything but in fact as Mike already mentioned people have actually found plague much earlier in time and they actually buy out the accident or coincidence started to look in population that lived thousands of years ago in the Stone Age in a very very interesting time period that we call the late Stone Age which was a time of large genetic changes all over um Western Eurasia so that's the time where together with with David's David Rice lab here and other colleagues also in Copenhagen we did a lot of research and looking at human genomes and trying to understand how the human genetic makeup in this part of the world changed as through time and we found that about 5,000 years ago there was a major genetic turn over in Europe in fact between 70 and hundred percent of the population of Central Europe at the time got replaced by a population of steppe pastoralists that migrated into Central Europe and all the way into the outside in fact this population here in the Altai is almost impossible to distinguish from this population very different from the previous populations we have this major expansion of people that happened during the time within very short time period maybe 100 to 200 years which is quite exciting what we then also see is even a backflow then after this major migration is a backflow of human genes into this region that cultures are then called sinter shannond runnable and we and a lot of other people people also here in the room have been thinking hard about what actually caused this major migration what is responsible for a large genetic exchange in kind of turnover of human genetic makeup so what happened was there some sort of climatic event was there warfare to what she happened during this time and and this is where our colleagues from Copenhagen had this wonderful idea to actually look for pathogens in the people from the time period and to our surprise they indeed found a pathogen and that they actually found was just senior pastors around here senior pastors in two individuals and some evidence and more individuals where they were even able to reconstruct complete genomes from one was from this afanasiev oh there's five thousand-year-old culture in the Altai mountains and one was from andronovo from the same region but about three and a half thousand years old so that was very exciting to us because now we thought okay maybe that was a time of pandemic already maybe there was a time where pathogens were spreading maybe they are kind of somehow responsible also for the kind of large net turnovers in the human population we then did our homework and looked in our samples that together with David we have been working on in the last few years for his senior passes and indeed we found it in quite a few of them and those are not actually coming from Europe and so we have been able to reconstruct no complete yet senior pastors genomes from Latvia from Estonia from southern Germany also from the yum niyam population in southern Russia and one also from Croatia in the Mediterranean now this is really exciting because now we can actually put the whole history and evolution of the pathogen even a few thousand years for the back of time we can put those genomes into the family tree of your senior pestis and actually you see that they're building their own branch inside the phylogeny they're actually on a branch that is slightly outside of the modern genetic diversity Falls basil it branches off early had branches of about five thousand five hundred years ago from the other senior pestis genomes and there's only about four mutations from the most basal one to kind of the most recent common ancestor so it's very very close here to this time period so we can basically assume that these kind of divergence of many of those strains started and happened at that time period so that's kind of the earliest spread potentially or evolution of the pathogen what you can however also see is that there's many of those little branches that are dead ends and the whole branch itself is a dead end so there's no it's in your pastures in the world today anymore that kind of falls on this major branch here so all the later ones fall on this branch here and don't seem to be related to this Stone Age branch what is also interesting is you can actually see this numbers here the numbers correspond to the age to the radiocarbon age of those samples we actually see this is the oldest second oldest third or the force or the spitballs if they actually kind of built little kind of branches here on the tree by time so it's really kind of an evolution of this pathogen over a thousand year time period and you can also connect them by arrows and if you do that which I know historians and archaeologists are never happy when we geneticist put arrows on maps but we sometimes still do that and you can actually see this is kind of the first the oldest one is from this kind of yam nya population then you have this one here in the Altai one from Estonia then North Latvia first and Estonia then you have outspoken south of Germany and then actually the last one is this andronovo here genome I'm from again the Altai region and if you look at this little map here that looks quite similar to this map right which is the movement of the people so really seems quite intriguing that basically the pathogen seems to follow a very similar route to what we also see in the human genome where we see this population yeah Maya expanding and then we seem to even have some flow back into Asia so again similar to also what we saw in the medieval time what is also quite exciting is we can now look at the genome structure so what you see here is basically the modern Ksenia passes in gray and then all those Stone Age genomes and you can actually look up their genes missing and for the chromosome we see almost nothing as a little gene missing here and as a gene missing there but then on one of the Plattsmouth which are extra chromosomes you can actually see there's this big gap here right and this is quite interesting because on this gap is actually a gene which is called ymt which is the gene that the bacteria need to survive inside the flea this is actually not present so from that we can actually hypothesize that this type of your senior pastors was not transmitted by fleas right so if you look at the basically three different forms that we know that bubonic plague is unlikely because it misses kind of the genes that are necessary for a free transmission which leaves us then Receptus emic plague which basically means that somehow enters the bloodstream however it does not by free biting or pneumonic plague you multiply however today is very very rare we don't really have many cases in the 20th century doesn't really happen that often so it's hard to imagine that throughout Western Eurasia there was a large epidemic in prehistory where it was all transmitted orally by droplet infection but it's not impossible and currently we can only speculate what happened how it was actually transmitted between people this afternoon we just had a long conversation with David and his team and we still really don't have a good understanding of what happened here how this disease actually spread in pre historical time periods so then in summary what can we say we can say a senior pastors cause dynamics in the past at least the three major ones the gist in Yannick plague the plaque death and the third pandemic were caused by Yersinia pestis maybe even earlier ones like the Antonine plague or the plague of Athens we can also say that it established a reservoir population in Europe at least in the time after the Black Death and probably also after that just in any plague what rodent we do not know um we can only speculate and as many interesting suggestions some of you might have also followed the literature on leprosy there was an amazing paper just a couple of months ago where people now found a reservoir population for leprosy that lives in Europe too that lives specifically in the United Kingdom and that is actually red squirrels which I probably pronounced wrong now sorry German is a Jean Genet those are very difficult but they found leprosy and lepromatous is the closest relative of leprosy in squirrel populations all over the United Kingdom it is actually very exciting because we didn't even know that there's a wild reservoir population of leprosy we thought it's just a human disease that's very very exciting we then have a European origin of this lineage one which is the major lineage you find for example the Grand Canyon today so basically the squirrels in the Grand Canyon that carriers in your pasture today where senior pestis rain that once was in Europe and through Asia get transmitted all the way into the west coast of the United States made its way into the Grand Canyon so quite a voyage at this pathogen she encountered and then cause basically this this third pandemic in the in the 19th century so we really see a high mobility of a senior pestis throughout human history throughout the last 5000 years at least and that is interesting because there's a rodent borne disease so we would really have to move the rodents with a pathogen which is kind of hard to imagine it certainly makes sense as soon as you have ships and you basically have ships as a vessel to kind of bring the disease somewhere this is how it arrives in California this is probably also how it arrives in the Mediterranean during the Black Death but at least in pre historical times it's kind of hard to imagine if people really carried rests when they were on the horses as pastoralists in the steppe it's kind of really hard to imagine and then of course there's all kind of possibilities this mobility in humans might like trade migration globalization cost and visited the dissemination of the disease and there commences potentially and then your senior pastors might have been already a major cause of pandemics in the past so we've seen it in the Stone Age probably we should really intensely now look also at those earlier historical outbreaks like the Antonine plague like the plague of Athens other large outbreaks at the end of the Bronze Age and the the Mediterranean so it's really possible that a senior passes has shaped human history for actually thousands of years starting in the Stone Age and actually all the way into the 19th century which i think is quite exciting with that I'd like to acknowledge many people here in the room and other collaboration partners also my entire department and group at the Max Planck Institute in Vienna a lot of people that funded the research over the last couple of years and thank you for your attention [Music] [Applause] Thank You Johannes for a tip through pathogens it's filled with verve and from new information very important to information very exciting let's begin our reaction with some thoughts from my good friend and colleague kyle harper senior vice president and professor of classes at the university of oklahoma rate is the son yes first of all thank you Mike and it's an honor to be a part of this and to be present at such genuinely exciting and really rare all-too-rare meeting of minds across so many kinds of and thank you Johannes for all of your work as a historian what you do is one of the most exciting things happening in the field and for presenting such an exciting overview of what we're learning about what I think amounts by by any estimate to one of the worst mass murderers in all of all of history and I just would start by putting into context a little bit of what you've said from a historians point of view how I hear what you're saying because I think historians should be paying attention to what you're doing not because it's sort of an interesting solution to a cold case this isn't an episode of unsolved mysteries to identify what caused these pandemics it intervenes in ways that should really challenge historians to reread the sources to to rethink the way that we understand the role of diseases in history and these great pandemics in particular and just last year one of the most eminent medievalists published a synthesis of medieval history that covered very briefly the Justinian plague and did so in a way that was entirely dismissive of its significance incited a very old now dated article minimizing the impact of the Justinian ik plague and claiming its narrow Geographic origins or near Geographic impact and unknown pathogenic cause and this was of course after the really remarkable papers of the last few years that have already taught this what in fact was the identity of the pathogen that caused the first pandemic as we called the plague of Justinian and so it not only tells us what your work normally tells us the identity of this bacterium that caused the great pandemics like the plague of Justinian and that that in turn helps I think to enrich and change the way we can read the historical sources and even at times frankly validates them are two main I witness sources to the plague of Justinian procopius and john of ephesus offer detailed descriptions of the pathology of the disease which should have led us all along to be very suspicious of your sonya but to have now molecular evidence that validates those historical sources is in itself quite important but the discovery of the molecular evidence for your sania pestis is the agent of the first pandemic is significant and another way to because of the location of its discovery i think all along the the hardest question in deciding what was the impact of the first endemic is knowing exactly how widespread its devastation was how deeply it penetrated for instance the western territories and places like the rural countryside where there were far from the cities no one who's read I think procopius or john of ephesus has any doubt that this was quite a destructive disease in Constantinople but now to know that it reached to Western villages of a few hundred people perhaps helps really in substantial ways to build the case that this disease was in a lot of the dark places on the map where we simply don't have any written evidence and so I think that the the molecular evidences strongly supporting a maximalist interpretation of the first pandemic so what you're doing is hugely significant but I want to offer to two kinds of questions one is what can the molecular evidence now or perhaps in the future tell us do you think about why the disease becomes pandemic i I think personally that there's a strong case to be made that the six shuri pandemic in the age of Justinian is the first true pandemic of the bubonic plague that it existed for thousands of years it had afflicted humans in various ways but the plague of Athens and the Antonine plague or very likely caused by other agents will time will tell hopefully with molecular identification but at present I'd be skeptical that those are likely to be caused by Yersinia pestis and so why then does there's a disease that may have existed for thousands of years cause what is clearly a disease episode that is on a scale unlike anything that if it caused before at least in the circuit Mediterranean and Western Eurasia or there's some combination do you think of ecological factors or genetic factors when you look at the Stone Age plague do you've already mentioned that it lacked the ability to produce the marine toxin that lets it build the the blockage and the the biofilm and the foregut that makes it such an efficient means of transmission do you think that there are evolutionary changes that lie right behind the just dynamic plague that might have caused it to become ten Demick in time and so what what do you think that the genetic events will tell us about that and then I'm second set of questions is maybe even a little bit more historical but I'd be interested what a genetic evidence might be able to contribute to our understanding of why does it happen then when it when it happens and why does it end when it ends and do you think that there is a case to be made for climate factors because we're learning that the five 30s and five 40s the moment right before the outbreak of the first endemic were truly exceptional moments in the entire span of the late Holocene they're really at the scene of violent climate turbulence and the the coincidence seems I'm not not incidental to the connection between the climate turbulence and the pandemic as well the 1340s also looked to be kind of outliers in terms of climate history and then as well the end of these pandemics and I think it was so interesting to hear you really talk about the way the Justinian ik line is an extinct lineage where is the Black Death leads on but both the the 8th century and then the the 18th century are also periods of warming and certainly that the end of the kind of late antique Little Ice Age and Cohen seems to coincide with the end of the first pandemic so do you think that the genetic evidence can help us understand the kind of deeper relationships and earth systems between pathogen evolution and climate history if so that's very good questions and I'm afraid that genetics can probably not offer any satisfying answers currently on that what we can say is that we don't see convergent evolution in the pathogen lineages that lend heed to the major pandemics so it's not a receive that certainly some larger kind of for example changes happen in terms of the plasmid structure that there no G new genes popping up that all happens in kind of the late Stone Age Bronze Age but that doesn't happen in in historical time period so the pathogen basically they cause the just in any place the pathogen they're called the Black Death the one that you find the Grand Canyon today I would think at least based on what the knowledge the biological understanding that we currently have of the plague had the same virulence it would cause the same disease if they if you if you cata pulled back the Grand Canyon pass pathogens medieval time it could potentially cause the black death again and the same would probably be the case for the Justinian in place so there's no reason to assume it was a biological change of the pathogen of course environmental changes are very important as your outline there was this major kind of climatic shifts in the 500 30s which probably cost starvation which caused devastation which probably also together maybe with earthquakes as people have suggested and and other catastrophes had an impact may be on the rodent population either increase stress on the rodent population or cause major actually explosions of the rodent populations that then after for example an earthquake people have suggested causes destruction they're actually good for the rodent population because they find a lot of food but eventually it's all eaten up the populations under stress and diseases can spread within the rodent population and then they can actually jump into the human population because what we always have to keep in mind for your senior passes it's a rodent borne pathogen that's actually a rodent pathogen so what we really have to understand better is rodent population dynamics and what's actually happened in the rodent population because that then affect the humans humans are just the byproduct of what's actually going on in the rodent rodent populations and they're I think we have to do way more research in the future it's very very little is known even how the root the pathogens spread within the rodent population how they can actually spread it through the commencer population even the kind of reservoir populations in Central Asia are not well researched and well understood because might be hard to find graduate students and want to study those animals or something I'm not quite sure but it's very little research and there's also unfortunately very little genetic data from wild rodent populations in Central Asia where probably the origin of the diseases at least what we think currently and so that's that's very very difficult but I think we really have to maybe talk more with ecologists people that study rodent populations that could then link kind of climatic changes we were again in a time of climatic change where probably we see certain patterns that might be similar we could potentially link those climatic changes to changes than in the rodent population but I think that is probably very important and the other thing might just be chance right why did it happen in the mid 14th century why has it happened in 6th century maybe what's just chance maybe what's just for whatever reason this rodent population and came into contact with kapha in the Crimea and then was transmitted by the January's into the Mediterranean by ships and interest basically spread all over the Mediterranean it could also be a trance effect I do think the Stone Age plague genetic evidence that we now have suggests that at least there were large outbreaks in the so this is why I also say about the Antonine plague and the plague of Athens that at least we have to consider plague now as the causative agent I think it's also based on the what Colleen and other people write it's probably not necessarily a play it could be a combination of many diseases but I think we have to know kind of really focus back on what happened in the past because what we have to in the Stone Age is quite amazing because in the data set at least that the group in Copenhagen analyzed about 10% of all the individuals they looked at head lake that is almost comparable to our elven mass grave right where we know everybody died of plague because of course when we look at ancient skeletons it is we probably have a eighty to ninety percent kind of false a negative rate where we basically don't find the pathogen but the heck she has been there and if you see ten percent actually half the pathogen you can actually assume it was way more common than we think it might have been so probably it was actually quite common and that's almost in kind of epidemic level but then of course what we also have to keep in mind as a thousand year time period that is not five years so I can the black death or so so I think it's a good chance that it was on a pandemic level already early on and if we have that in the Stone Age then there's a very good chance that happened also in the later metal ages or even in earlier antiquity so I think we really have to keep our eye now into this directions another one another interesting fact that I'm trying to do now with some colleagues is um if you look at the phylogeny you seem to see often those events like this event with a black death we have the star like phylogeny you have many many strains diverging from each other we also have that here in fact there's a bunch more here as a bunch more there if many things kind of spreading at that time we should actually look into the tree if you find other events where a lot of things are spreading and now that we have a good timing of when things happen here maybe we actually find that something happens in the fifth century BC which kind of then points us towards the flag of Athens or we might actually find something even at the end of the Bronze Age is something where we see a lot of things that were urging that would be of course quite exciting because then we could actually use the molecular evidence to find the prehistorical or historical events and trying to find even more evidence based on the modern data that we already have which would be quite exciting and the word biomolecular evidence perhaps we can invite professor Benjamin to come offer a few thoughts to our some discussion before we take a few questions from the audience and move to Thank You Johannes that was just a terrific yeah you've really set the mark I think for future investigations using ancient pathogen genomics as you've described it and I think the impact that your work has is not limited of course to to historians of the Roman Empire but more broadly to let the Denix of the past and surely there's no shortage of good questions that come to mind based on your work I'd like to raise just a few and I realize that they're probably no short answers no immediate answers to any of these so I don't want to put you on the spot but I'd like to there's one question that I have that I'll raise in just a few moments that I think actually goes beyond the reach of ancient DNA research and the industry to get your reaction to that but I want to begin with one that's closer to home about the work you've just presented and that has to do with crispers and I think crispers are known to the general public through the all of the news about how the impact of CRISPR technology reaches out as a therapeutic revolution really in genetic engineering but I'd like to put that aside and sort of focus back on crispers in their natural setting which of course is low sigh in the bacterial genomes which are a record in short DNA sequences of the sort of the infectious history of the pathogen of the bacterium itself these are short sequences that represent that derived from bacteria phage or invading plasmids that are pathogenic to the Yersinia bacterium and these are fossilized in the genome of various strains and I know that that's in some in some descriptions of your sania Crispus there's some that are commonly pseudo tuberculosis which as you point out as the ancient originally so could these be useful in fine-tuning the migrations of your Sandia the evolution of it the distribution of it and what am I just stop there and get your reaction to that and then I'll return yeah I mean there's very little also I can I can say about that because nobody has done that yet so I think that's very exciting that is very interesting to actually look at the kind of imprint that you might actually find in the genome of those bacteria but nobody has kind of looked at that now of course if we look at this family tree and the genetic differences we have here you can count them on two hands they are very very few and so I think what you kind of might find even if you look at the plasmids you can't even build this phylogenetic tree on the plasmid so doing that on the CRISPR some kind of trying to kind of reconstruct some history goes really deep into the history of this pathogen maybe kind of how it came out of this to do tuberculosis cloud because powerful ethics with one tiny branch in the to do tuberculosis family that has very is much much more diverse so I think that's more kind of addressing than the kind of deeper evolution basically of the pathogen but nothing that would be able to address for the last 2,000 years because there's too little genetic changes maybe it's hard for me to imagine how your senior which migrates through rats and fleas and humans that wouldn't cast some light on the micro revolution and dispersion of that so there's a second class of questions which I think in many ways is broader and also technically more challenging and that has to do with epidemics due to viruses you mentioned in your talk several examples of past plagues that has questionable associations with viruses and I'm thinking mainly about RNA viruses where we certainly don't expect the RNA persist in the ancient remains so how do we approach the question of searching for causes due to RNA viruses and thought that you and I actually have discussed once at least briefly in the past so is can we use the human DNA of the victims and recover the antibody genes of those victims and test them against modern pathogens Yersinia being so it seems to me that going to your the human DNA libraries from the victims of your scindia pestis which you've studied and those be used those libraries to use to identify and amplify functional IgG libraries that could be tested against against modern arrays which is a very intriguing idea I think problem currently is that most of our genetic data comes from bones and specifically comes now from Petrus bones which the inner ear which is actually a form of bone that doesn't change much after kind of birth so it's very very stable and and the osteocytes would probably not be the source of the type of genetic information that you are looking for so it would only be if you would have some sort of I guess white blood cells which you would find baby inside teeth may be inside infections potentially one could look into caries for example which is some sort of infection where you have a lot of white blood cell activity maybe also some other lesions on the body but the problem would probably be I could at least see is that you have a whole group of different types of cells that this DNA actually derives from and only a few of them actually carry this rearrangements that one would like to study so because you get the soup of DNA from all kind of different organisms would be very very difficult to to reconstruct then this kind of rearranged genetic signatures which would actually then be useful to reconstruct a past and has exposure to to a certain pathogen so I probably would think that it would then give more likely to say find the proteins themselves or something in order for the immunoglobulins or something like that that is something I think when when one should try and I think people we have been discussing that in the past and it's something that I think one could probably do maybe going from the 19th or 20th century medical collections kind of further back in time let's start with Neanderthals like people tend to do but yeah it's certainly I think I think the going forward with investigating that question depends on the quality of the human DNA and the amount of vascular so the pet is a Petrus bone highly vascularized you don't know though it's not that's not okay so that yes unfortunately because that that is also where the preservation was so fantastic because it is actually very dense very very inactive bone in fact yeah well I just think that using your material where we start out with known victims of whitey that would be a favorable one to test this hypothesis so a final question that's been raised often by infectious disease historians and modern-day immunologists is whether major outbreaks of plagues let's think the black death as an example imposes a bottleneck a genetic bottleneck on the human population this was raised I think in part of your talk when you discuss this it seems to me that if the human DNA is of these victims can be looked at and particularly the MHC locus which is the main determinant for pathogen recognition and the UN response that this might be a way to actually answer that question or at least investigate it has there been a shift in the MHC pre and post outbreak no that is a very important question so the one that I addressed at the beginning this host pathogen into action trying to understand also how the human population react isn't is they actually immunity and going back to question about why did it happen and how did why did it happen so so kind of strong at the beginning at the Black Death and the Justinian plague maybe even in a Stone Age there was very high mortality and then the cat kind of went down through through the centuries probably because immunity was building up but this is just the adaptive immune system or is it actually the inborn immune system like HLA for example or pollak receptors or other genes that give you some sort of immunity and people have been speculating about that a lot already more than 10 years ago people are send some exciting research whether it suggests that there are certain mutations like the ccr5 mutation that gives you also resistance against HIV and people have actually suspected because in high frequency in europe it might have been actually also giving you resistance against plague but then other people actually part of the Betty here who's also in Harvard now actually showed that it's actually a very very old gene it's not just kind of rows and frequency in the last a few hundred years so there has been much speculation but so far we haven't identified any gene that is basically giving you immunity or something that has been under selection due to the plague HLA would of course be one obvious locus we have actually started the project some years ago to do exactly the type of question but back in the day we thought the Black Death was the first pandemic because the just in any plague didn't really look like a place for us in this kind of early genomic data set then we had to learn to just in any place was already plague so all those samples we collected from the pre Black Death were not useful anymore because the plague had just happened a few hundred years before so the lecture would have already been there we then started to collect material from the four centuries who then learn that it was already there during the Stone Age so now we would have to go back to the Stone Age and compare a pre kind of late Stone Age population to native population but then there's all kind of pathogens that kind of might have been responsible for genetic shifts and together with David and Ian Matheson one of his postdocs we actually had a study just two years ago where we showed that there's a whole bunch of immunity related genes that have been under selection and changed to the last eight thousand years but which one of that might be - plague is very difficult to say so currently we have a project where we're looking into victims of the Black Death trying to see they are somehow genetically different to people which city on the rooms wipers of the play but that is something that is still ongoing and so far we haven't found any hot candidate inside the HLA and also among the other 400 immunity genes that we are studying which could actually give some sort of immunity but we are kind of certainly very very excited and interested in the type of question thank you very much to Thomas and Johannes Hannes you're still standing could you kind of handle a question or two first are you after then let us invite questions from the audience human remains yeah with your directly dated human remains have you tried to calculate the pathogen mutation rate and if so is it faster or slower than you would have expected um so actually this tree which is a bit of a mock-up tree because it's not the extra tree that comes out of the software is based on those mutation rates otherwise we couldn't busy do the molecular dating here and actually we have so many calibration points of the molecular clock now inside the tree that we can actually get a pretty good one we have a pretty good understanding of the of the the pattern actually the the mutation rate turned out to be faster than was thought before so people actually thought that kind of the most recent common ancestor was something like twenty to thirty thousand years old we now show there's actually just five thousand years old and there's also things in the tree which I didn't really give names to here but some of them are called for example Antiqua some of them are called Madhubala's some of them are called Alliant eyeless which are all names from the 1950s where people first started to identify those differences in the different bacterial lines based on growing on different media and they gave them those names based on the three and AMEX and that is actually antique one year for example but there's also not Antiqua here and there's an antique were there and kind of doesn't make sense at all with the kind of branching pattern that we now have but that was also kind of showing that this is this and a-three has changed quite a lot now now that we have those ancient pathogens as calibration points and it's actually quite useful if you for example look at tuberculosis people had suggested that tuberculosis was more than 100,000 years old and came with humans Out of Africa has has been big papers Nature Genetics only two years ago and then when we actually got the ancient tuberculosis genomes plug them in the family tree we could actually see is only five thousand years old actually the same authors with us been on this other paper that we then publish where we could show knows only five thousand years old the square is very useful to have those ancient pathogens because you really can anchor the whole tree in time which people cannot do based on just studying in vitro bacteria I mean as for perhaps one more question because unbeknownst to you this man is really amazing not only is his science amazing and this is delivery in English amazing but he just got off the plane it's one o'clock in the morning for him and I think he's doing a hell of a job one last question and then we can continue the conversation with the glass Malcolm we need please Thank You Malcolm Weiner your honors thank you very much good to see you again professor Harper mentioned that of course the Justinian juice in Yannick plague especially in Constantinople is one where we know the number of casualties and in absolute terms they were very large but of course it's only in the Roman Empire that you begin to get populations again equal the population say of Egyptian Empire the Hittites and of course in Crete where I just a doctor press of paper today it looks as though the population goes from about 300,000 people at the height of the moon own empire down to about 60,000 which is you know an eighty percent fall so in relative terms that's very great now of course Herodotus tells us that the the descendants of the ancient cretins told him that there were two terrible plague episodes went just before the Trojan War and one after but we know of course Mali Hittite acts and the Egyptian texts that they speak endlessly about the horrors of the plague the Hittites fall at the Egyptian plague but it takes two successive kills through successive tight Emperor's and Rameses the fist is thought to have died of famine ation skeleton so as the question arises whether we didn't have plagues in the Bronze Age that we're just as serious we know we know from the texts we got you're more varied so I tried to send plague infected sheep behind the lines of the others but it's really very hard to know whether these citizens even in absolute terms certainly in relative terms we're not as destructive as the semiotic plague and indeed the Black Death there's no absolutely and this is actually exactly what we're trying to address also with this new research centre that we want to try to find out what caused those major kind of cultural turnovers and probably also genetic donors at the end of the of the Bronze Age in the late 2nd millennium because yeah we have major devastation we have things happening all through the eastern Mediterranean probably the Mediterranean at that time and and there has been much speculation was it just the sea people was just people moving around or what cost and then to move around in the first place and was it may be also diseases that kind of spread during that time and you could probably ask that for many of those time periods and fact we have some unpopular is very exciting data and now also from the Bronze Age but we actually have two nodes now following on this part of the author of the tree so things that have actually the flea transmission that caused bubonic plague so I think we move this entire kind of bubonic story now also into the Bronx Age and then it's well possible that the hittite plague or some other place we know from that time period might actually being caused by bubonic plague so it's something that now everything all the human remains that that we are collecting current also checking for in fact not just one a place but actually for more than 150 pathogens currencies where has been a large screening one of my postdocs for 3,000 human remains 450 pathogens we found about 450 positive hits throughout the last eight thousand years or all kind of things that the whole kind of new field that is emerging now especially with this new computational approaches that we can we do some sort of health check I mean we have to assume that most people that died in the past didn't die of old age but in fact of some infectious disease so many that we certainly I mean it causes people to be immunocompromised some extent if they're kind of starving and I mean that would be know from the from many kind of families in the last 200 years and that's certainly a very very important point as well as that time period that pathogens might have a greater chance to spread like we discussed before the 500 30s or also in the 14th century before the Black Death there were major famines in Europe miss harvest for several years especially the beginning of the 14th century which probably had their toll on the on the population and might make it them easier also for those pathogens spread I propose that we give professor Krauss a resounding round of applause [Applause]

Channel: Science of the Human Past

Views: 14,337

Keywords: SoHP, Johannes Krause, Ancient DNA, Roman Empire, Plague

Id: ywlXj46SeUg

Length: 97min 49sec (5869 seconds)

Published: Fri May 12 2017