DNA from hunter-gatherer teeth reveals secrets of ancient plague

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1:02No idea. But now the data's... I find this not only refreshing, but at some level astounding. Nature.

1:15Welcome back to the Nature Podcast. This week, investigating plague outbreaks in ancient hunter-gatherers. And a prototype dark matter detector. I'm Nick Bertridge-Hell. And I'm Benjamin Thompson.

1:38Plague, a disease caused by the bacterium Yersinia pestis, has devastated humanity, causing the deaths of millions of people over millennia. But not much is known about ancient plague, something a new paper in Nature is shining a light on. Now, there are actually a few different types of plague, and they're transmitted in different ways. But the one that everybody immediately thinks of is bubonic plague, transmitted by the bites of fleas. It's the cause of the Black Death, a pandemic that tore through Europe and parts of Asia in the Middle Ages. But evidence suggests that Yersinia pestis only gained the ability to be transmitted this way about three and a half thousand years ago.

2:23There have been much older cases of plague discovered in human remains, dating back well over five thousand years. What this older plague was like, though, is something of a mystery, and researchers have been debating things like its genetics and how severe it might have been. This week, though, a team of researchers have been trying to answer some of these questions. They've been looking at evidence of ancient plague infections in hunter-gatherers living in a resource-rich area around the enormous Lake Baikal, in what is now Siberia. To find out more about what they found, I spoke with one of the team, Ruri McLeod from the University of Oxford here in the UK.

3:05Ruri laid out to me a little bit more about the site and where the remains were found. So this is a great place to be a prehistoric hunter-gatherer. And so we see really, really long-term presence of humans living around Lake Baikal. We're looking at four burial grounds that have been reused by these hunter-gatherers. This is around about 5 ,500 years ago for the oldest site. The oldest pair are Ustida I and quite close to that is Shumulika. and then Bratsky-Kamen and Sarovo. And these sites are separated by hundreds of years? Yes, so these sites are separated by centuries. And so what was quite exciting about this large cemetery, Ustida 1, was that there was a real mystery around about the mortality profile of the individuals that the archaeologists excavated at that site.

3:50A lot of teenagers, basically, a lot of adolescents, a lot of older children, far more than you would usually expect for a cemetery of that size. And so it was clear that something was causing this high mortality of these younger people. So it was super exciting when we managed to find such widespread evidence for infections of plague amongst these individuals. And you were researching these people and you did, as you say, find evidence of plague infection. How did that come about? So for the most part, what we were doing were we were taking teeth from the archaeological remains of these individuals, taking a very, very small amount of the tip of the root of some of these teeth and grinding that down, and powderising that to be able to dissolve it and extract purified DNA to look for evidence of these individuals' own genomes, as well as anything that they might have been infected with, like plague.

4:37So across these individuals, we've got a 39 % detection rate of plague. So obviously, a lot of the time, pathogen DNA doesn't preserve very well. It's a very, very small component of the DNA that we'd expect to get in these remains. And so frequently, we find that we have false negatives, quite high false negatives for some diseases. Just as a comparison, we have lots of sequencing data from medieval plague pits in London. There's one at Smithfield site, and there they obtained a detection rate overall of 20%. But that's within a medieval plague pit, where you'd expect 100 % of the people pretty much to be infected with plague.

5:12So really, the fact that we're getting 39 % 5 ,500 years ago, thousands of years before this medieval plague pit, is an incredible result in itself and would be consistent with pretty much everybody potentially having died of plague. So broadly then you have these four burial sites separated into pairs in terms of how old they are with a gap in between them, suggesting the outbreak of this disease happened more than once? That's a big question. Is it something that's been maintained in the Baikal population over a few centuries or is it just spilling over again from a wild animal reservoir? And I think it's almost certainly spilling over again.

5:47We can see that there are slight differences in the mutations present between these two strains and if it's spilled over once then it can spill over again from the wild rodents that are around about lake baikal there's kind of two avenues here then you have evidence that the plague bacterium was found in this group over quite some time period potentially different outbreaks and there is what you learned about the genetics of the yersinia pestis plague bacteria but of course there are people at the heart of this what did your research tell you about the folk who were interred at this site. So really, because we got the genome data from the humans as well, we were able to reconstruct the biological relationships between these individuals.

6:25It was kind of really touching in a way to be able to see how these people had clearly been buried by people who knew their relationships in real life. So we saw lots of cases of siblings being buried together in the same grave, apparently having died at the same time. We saw cases of parents buried with offspring. Actually, there's one particularly interesting case where a young boy and a young girl both in their teens were buried in the same shared grave and looked like they'd died a plague and they weren't closely biologically related at all but that really nicely hinted at some kind of other relationship that they might have had in life that determined their burial together in death.

7:03And in terms of the genomics then you've taken the genomes of these ancient plague samples and compared them with other strains of plague bacteria and also of a related bacterium called Yersinia pseudotuberculosis which can cause a severe but often less serious disease. Yes so one of the exciting results was that we found this particular gene associated with pseudotuberculosis but not with Yersinia pestis with plague called YPM and so this is a unique instance of a super antigen in a gram negative bacterium which is a lot of technical terminology but effectively what that means is that you have a gene which stimulates a lot of different immune responses at the same time and increases the likelihood of a vast overstimulation of immune response, which causes very severe symptoms for the host who's infected with this.

7:54And so essentially what I think is going on is you have the worst of both worlds from the genes from pseudotuberculosis and from pestis present in these plague strains. And so that accounts for why we see this particularly high mortality amongst young adults and young children who potentially are more vulnerable through not having fully acquired their adaptive immune system and are also less likely to have been exposed to this before if previous infections had occurred. You've got an idea there then of why it may have been so severe in young people. Do your results give you any idea as to how it might have been transmitted?

8:31We can't help, I suppose, but think of the bubonic plague spread by the bites of fleas. So we know that the bubonic plague, as you say, was transmitted by flea bites, and that's kind of mostly mediated by this particular adaptation that plague gets from around about 3 ,500 years ago, where it acquires a gene called YMT. All the evidence from Baikal and from plague strains before 3 ,500 years ago is that they don't have this gene and therefore they can't be transmitted via this pathway. The other options for plague infection are pneumonic plague and septicemic plague. So pneumonic plague also has a terrible history.

9:05It's responsible for tens of thousands of deaths in the Maturian plague outbreak in China in the early 20th century. And it's highly transmissible by coughing spread by aerosolized droplets. And that, to my mind, is the clearest explanation that we're seeing at Baikal. We have a good amount of evidence suggesting that it did spread from person to person because we have so many biological relationships amongst these people and we have kinship networks and biological relatedness between sites as well. And what about where they may have got it from? The thought to be the natural reservoir of plague is the marmot.

9:38And marmots are the kind of primary reservoir known in Central Asia and in Mongolia. The question is, how might plague have infected humans from marmots five and a half thousand years ago around about Lake Baikal? So we know that the humans are interacting very closely with the marmots as hunter-gatherers. We see sites where there's lots and lots of marmot teeth, marmot incisors being curated as grave goods. So they probably came into contact enough for humans to have been infected by marmots. How that might have happened in the absence of flea transmission would potentially make sense in the context of eating undercooked marmot flesh.

10:12And then that has been known to lead to mnemonic transmission of plague as well, which would then explain large-scale human-to-human transmission across available hunter-gatherers. Now, there were lots of questions about ancient plague as a disease. What do you think this work does to address some of them? Well, first of all, this is the most compelling evidence that we're ever likely to gain, that these early plague strains were lethal and deadly. And that kind of really puts to bed in my mind that long running debate as to how lethal and how much of an impact on populations did these early outbreaks of plague actually have.

10:45Secondly, the fact that we find these in prehistoric hunter-gatherer communities, and we find repeated spillovers in these prehistoric hunter-gatherer communities, evidence is that they face the same challenges that their farming contemporaries or neurocontemporaries in Europe would have as well, and shows that we should reconsider the assumptions around about lifestyles for risk of zoonotic disease spillover. And then finally, I think that in terms of understanding the genome evolution of plague, Having this data and having presence and absences of genes, being able to understand the patterns of gene loss and gain is kind of really, really interesting in better understanding the origins and evolutionary history of a disease which has been so successful at killing lots and lots of humans over the millennia.

11:29So you're seeing evidence of plague outbreaks among a somewhat disparate group of folk. They're not established in a town or a village. And there has been this idea that living in this more settled manner, alongside being in close proximity to animals, to livestock and what have you, is what's important for disease outbreaks. There are folk, of course, for whom the latter is what their evidence suggests happens. What do you think they'll make of your evidence? Well, you can quite easily dismiss this as just a one-off, like, this is an exception to the rule, but doesn't necessarily disprove the rule at all.

11:58I think they would say that more data is needed from the missing longue durée of the Neolithic. So, you know, the Neolithic spans from about 10 ,000 years ago in Western Asia and in Europe. And we have very little data for zoonotic pathogens across most of that time period. So more data is needed, I guess, would be the main concern. And finally, then, what questions remain, do you think? So, I mean, this is just concentrated in a single site. And so all of this kind of missing data that we have between Baikal and between the next outbreaks of plague that we're aware of in late Neolithic Europe, I mean, it's about 5000 kilometres away or something.

12:34It's a vast expanse of northern Eurasia. But we don't have any data for that in between region. We don't know how it's being transmitted. So I suppose you could have a lot of theories as to consistent overspill from lots of different species of rodents and similar animals. Plague is constantly sweeping through that population of wild animals and occasionally spills out in Baikal and occasionally spills over in late Neolithic Europe, in Latvia and in southern Sweden. Or it could be something like migratory birds. That's also been a suggestion. But really, we don't know. And we really could do with better data to be able to answer that really compelling question.

13:11Rory McLeod there. To read his paper, head over to the show notes for a link. Coming up, researchers have been figuring out how to use atoms to detect phenomena in space. Right now, though, it's time for the research highlights with Katrina Clark.

13:29For one Iron Age woman, death wasn't the end, as it appears some of her bones were whittled to sharp points, potentially to be used as tools. Researchers looking at Iron Age individuals buried in a cairn in Scotland discovered a female, at least age 30, and a male adolescent buried together. By analysing the remains, a team discovered that the pair had died sometime between 50 BC and 70 AD and that they were related. The male's teeth suggested that he'd lived through periods of malnutrition, while the female's skull had cut marks inside it, suggesting that her brain had been removed shortly after death.

14:05Three of her arm bones and one leg bone had also been sharpened, which the researchers suggest may have been done to use them as tools. While to a modern ear, this may sound like desecration, the team says that her skeleton was carefully reassembled, indicating she was actually a respected member of the community. Exactly why this was done remains unknown. You can dig into that work over at Antiquity.

14:35To survive years without eating, some giant deep-sea crustaceans have taken a note, and a gene, from bacteria. Supergiant bathynomids can grow up to 50 centimetres in length, that is in spite of living in food-scarce deep-sea environments. In fact, some species can survive five years without eating. To find out the genetic basis for this far-reaching fast, researchers looked at the genomes of two of the species, Bathynomus Jamesy and Bathynomus Dodelani. They found that both of them harboured numerous copies of a gene called ND1 which was acquired from a bacteria more than 16 million years ago.

15:14The team also trialled this gene out in zebrafish and found that when deprived of food the fish would have reduced metabolic rates and their survival was boosted at lower temperatures. This suggests that the Bathynomids can reprogram their energy allocation balancing the demands of their giant bodies and the need to suppress their metabolism in extreme environments. You don't need to survive for years without reading this work. It's over in Cell.

15:44Next up, researchers have made a prototype that could help them probe the mysterious dark universe and even dark matter. To understand how it works, let's go back to 2015. back then a discovery shook the astrophysics community for the first time ripples in space time gravitational waves were detected they were picked up by ligo a large laser interferometer a device that takes a laser beam splits it in two and fires these down long arms ordinarily these split beams bounce off mirrors and return at the same time cancelling each other out however if say some disturbance in space-time, a gravitational wave, passes through the interferometer, it lengthens or shortens the arms a tiny bit, meaning the lasers stop cancelling each other out and hey presto, a gravitational wave has been detected.

16:43These ripples in space-time have been observed many times since and continue to allow researchers to understand phenomena in space that cause them, like the collisions of massive black holes. But these laser interferometers have their limitations. They can only detect waves at certain higher frequencies, meaning that they can only really detect phenomena like massive objects during their final collision. To tackle this, space-based laser interferometers like LISA are actively under construction, but even these will be limited to a lower band of frequencies. With the higher frequency detecting ground-based and the lower frequency detecting space-based interferometers, it means there's a gap in the middle that needs filling.

17:32Enter atom interferometers. These, in principle, work in the same way, but instead of looking at the difference between two lasers, it would look at the difference between atoms. By putting atoms into superposition, physicists can identify if there has been subtle alterations to their quantum state, like if a gravitational wave or even dark matter has passed by. It's something researchers have been trying to achieve for a while, but now in the pages of Nature this week, a team have demonstrated a prototype that could be the foundation of atom interferometers of the future, which could then help researchers observe all sorts of phenomena in space, we'd otherwise miss.

18:15This atom interferometer works with strontium atoms, which have a helpful feature for physicists. They can change their state at regular ultra-precise intervals, known as clock transitions. These allow time to be measured incredibly precisely, and by using two groups of these strontium atoms, researchers can see if one has undergone a clock transition at a different time from the other? If so, something has rippled space-time and you've just detected it. I spoke to Oliver Buchmüller, one of the prototype's builders, who told me what sorts of things these atom interferometers could find. To start out with, actually the first stage in our program is not so much gravitational waves.

18:57These instruments are very well designed to explore what I would call the dark universe. You know that basically around 95 % of the universe is unknown to us. And in particular, interesting aspect of this is that out of those 95%, roughly 25 to 30 % is believed to be what was called dark matter. Now, dark matter can come in various different incarnations. We don't really know. We haven't detected it yet. And one potential interesting incarnation is what we call ultra light dark matter. This is when you don't think of it as a particle anymore, but more like a classical wave that surrounds us every time any interaction takes place, this classical wave would be there and it would interact with us now as we speak, but the interaction is so soft and minute that we wouldn't realize it and we don't have the instrument to measure it.

19:48An atom in the formator is a perfect instrument to measure that if then this dark matter would be realized in nature because that dark matter would directly interact with my atoms and leave a change in one of those arms with respect to the other one, which I then can measure back. And so if a gravitational wave or something like that you wanted to measure passed through this, what would you detect using this? So what we would detect is basically the change of one of the two arms of the atom in the formator where the gravitational wave is impacting because what the gravitational wave will do, it will change the space-time continuum.

20:25In particular, it will change the length of our space-time continuum and therefore one arm will see a smaller length than the other arm. And for the atoms, this is then being imprinted by a change of time. Because the speed of light is a constant, that means a change of the space-time continuum in length translates for the atoms into a change of time. And that is something we can measure back then when we are looking at the atoms and the so-called atom interference patterns or matter fringes. And, you know, this sounds, I guess, on paper, fairly straightforward, but I understand that actually getting these to work is quite tricky.

21:03Can you talk me through some of the challenges involved in trying to get atom interferometers to work? One of the major challenges obviously is that it's a relatively new technology. I mean, obviously people talk about quantum computing a lot, but what is often forgotten is that the more mature quantum technology mankind has developed over the last 20 years is quantum sensing. This is in particular atomic clocks, but also atom interferometers. And what we do actually is to combine the enormous success that atomic clocks have had in the last 20 years. So what we would like to do, because we need enormous precision for measurement of gravitational waves and dark matter, is to combine this enormous precision of atomic clocks with the tool of atom interferometry.

21:48So how do you go about combining these two together? So it is basically the atoms itself. So you have, for example, in our case, a strontium atom, which has very special properties. It has what's referred to as a clock transition. And the reason why it is called the clock transition is because that transition between a state and another state has been used to build this very precise atomic clocks. And this clock transition, we now have basically transported over into atom interformity for the first time that this has been demonstrated in this paper. And so thinking about those two arms again, like is it a case of looking at whether the transition has occurred in one arm versus the other and then that would show that there's been a change in time as if space-time has been rippled?

22:31That is correct. Now there's a big problem which is the second aspect of our paper is if you only have one atom interferometer meaning two different arms you will have to communicate between the two different arms with a laser beam. That's how you are basically reading out the information. But the laser beam is noisy. There's a lot of noise on this laser beam. And if you are not able to cancel out the laser noise, as we call it, then all the information will be washed out, at least to the level of precision you would like to have. So the second part we have been demonstrating is that you cannot only operate one atom interferometer, but actually two atom interferometers, which are separated from each other.

23:13and they are then interrogated with one laser beam. And the fact that you are measuring two atom interform meters means that you can compare these two atom interform meters and subtract out this laser noise and therefore measure back the signals you would like to be interested in, which would otherwise not be possible. That's the other key demonstration of the Nature paper. And as I understand, this is a prototype. So were you able to actually use this to study phenomena or was this just we can do this now? This is really prototyping. So this is for the first time demonstrating the technology, which will be the base technology of scaling this up to instruments on the 10 metre, 100 metre, but eventually kilometre scale and possibly even bringing it up into space.

23:57So that prototype happened in the laboratory, but it is always important to demonstrate that you actually can do this on a smaller scale because then scaling up in itself is a challenge, but obviously you're building on a foundation in which you have already demonstrated the fundamental principles of your measurements. And so how would you go about scaling this up and what sort of challenges might you encounter? So, in fact, the interesting thing is that at CERN, we have been invited to write what is called a technical proposal for 140 meter atom interform meter based on that demonstrated principle, which would be then a real large-scale atom interferometer instrument which could be installed in one of the support shafts at CERN which would then have the capability to start exploring this ultra light dark matter and possibly even reaching already into the sensitivity reach of gravitational waves in a new frequency range but that is still something we would need to demonstrate.

24:55And so is that then the end goal to have something like 140 meters apart or is the goal to go even bigger in the future? Even bigger. If you really, in earnest, want to explore gravitational waves on Earth, you will have to scale this up to the kilometer scale. That is something we are already very actively looking in. So for example, I don't know how familiar you are with Switzerland, but there's a so-called Götter Tunnel, which is one of the important connections in Switzerland, which is built into the mountains. And it has two support shafts. One support shaft is almost the kilometer deep. And we are working with the Swiss Railway to see if such an atom interferometer in the longer future could be installed there.

25:35And so what would you say is your hope for this research? I think the biggest result we have been documented in this Nature paper is that the technology now is prototyped and is ready to be scaled up. This would open up a completely new physics program across the globe, because the idea would be not to just install one of those are two meter four meters, but several which are working in synchronous operation that will give you a much better coverage of, for example, gravitational waves. Most of the astrophysical sources in that frequency range, which we currently cannot measure because we don't have an instrument, will have lifetimes of days, weeks, and months.

26:13So this means I can follow that signal to make very precise sky determinations of where these signals are coming from. And that enables what we call a completely new landscape for multi-messenger physics, meaning that you have different instruments like telescopes, but also neutrino detection systems and so on. You can point in this direction and you can tell people, look, in a day or two, there will be a signal coming, be and get ready. That is currently not possible in the LIGO, Virgo environment, because what we see with these instruments is only the final chirp. It's a very, very, very short time when we see a signal, so we don't really know where it came from.

26:57This will be a complete game changer and could, yeah, open up a completely new way of looking on gravitational waves and multi-messenger physics. That was Oliver Buchmuller from Imperial College London in the UK and CERN in Switzerland. For more on that story, check out the show notes for some links. And that's all for this time. If you want to stay in touch, you can reach us on email, podcast at nature.com, or we're on social media at nature podcast. I'm Benjamin Thompson. And I'm Nick Petra-Chow. Thanks for listening.

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