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0:00
I totally thought this was a joke. You thought it was a joke? I'm, of course, from Sweden, so I know many people in Sweden. There was someone speaking Swedish calling me, claiming that he was from the Nobel Committee. And I thought, "Oh yeah, yeah, sure. Tell me more, tell me more. And like, after 30 seconds, it started sounding too serious. I started realize this may not be a joke. I'm Insoo Hyun, Director of the Center for Life Sciences at the Museum of Science. Today my guest is Svante
0:29
Pääbo, the Founding Director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. He won the Nobel Prize in 2022 for his work in ancient genetics, which includes sequencing the Neanderthal genome, and discovering a whole new group of ancient humans called the Denisovans.
0:48
Svante, it's so great to have you here on our program. Thank you so much for joining us. I'm very happy to be here. You know, you and I met a while ago in 2017. It was at a conference at Cold Spring Harbor, where I know you've been there many, many times. It was a brain organoid conference, and you gave the scientific keynote, and I gave the ethics keynote. And that was the first time I actually heard you in person speak about your work so eloquently. And I remember
1:14
going back to my room at Cold Spring Harbor and just staring out the window, just thinking about what you said. About human migration and the mixing of human with early human hominins. And, uh, it was just it was one of those moments where I thought, I didn't really appreciate, or it didn't sink in until then, how significant your work is in how we think about ourselves and how we think about human life. So I'd love to just get into the conversation with you
1:41
about your key discoveries, your key work. In 1997, you and others sequenced the mitochondrial DNA of Neanderthals. And then in 2010, you led a team that sequenced the entire nuclear DNA, the nuclear genome of Neanderthals. And it was also that year that you announced the discovery of another group of ancient humans called the Denisovans. Um, and so what I heard from your talk in Cold Spring Harbor and ever since then, was the fact that there's been a lot of mixing between humans,
2:10
what we call humans today, modern humans and these earlier, groups. And that we can trace that DNA even today in people's DNA samples. What does that tell us about how human beings evolved? I think the simplistic picture that a lot of kids get in school is that if they do teach evolution at all, it's about a very smooth, singular progression, very, very from a single common ancestor. And that's how we got to who we are today. But it's much more complex than that, right?
2:42
So in terms of the sort of origin of the direct ancestors of everyone alive today, what we call modern humans,
2:52
that's sort of ancestral populations, which probably also grew to populations with this transformation to modern humans happened in Africa. But at that time, one was not alone on the planet. Of course, there were many other forms of humans around them. And that is actually typical, I think, of human evolution, that there was almost all of these different forms of humans around.
3:15
And these modern humans know two, three hundred thousand years ago, spread across Africa and spread out of Africa and met these other groups. And what we then found out when we studied the genome of our closest evolutionary relatives and Neanderthals, is that one mixed with each other when one met and actually had babies, and those babies were successful enough to be incorporated into modern human societies and in turn have babies such that, for everyone
3:48
whose genetic roots are outside Africa today, carry 1 or 2% of the DNA that comes from Neanderthals. So many of us today, sort of,
4:01
Neanderthals live on a little bit in us, so to say. Yeah, you've written what I thought was so beautiful. You said "Neanderthals are not completely extinct. Their DNA, some of their DNA still lives within us". And I think that's wonderful. Yes, because sort of each of us carry different fragments of the Neanderthals, you know, across our genome. So if you sort of jump from person to person, we can see how much can we parcel together of the Neanderthal genome in people today.
4:31
And the jury's a bit out on that still. But at least 60% of the Neanderthal genome is still walking around on two legs, so to say, today. So they are not totally extinct. They sort of live on in many of us still. That's wonderful. So it's not just the Neanderthals, there are the Denisovans. It looks like maybe the Denisovans and the Neanderthals also mixed.
4:53
Um, and then human, maybe the Denisovan DNA is also found in human especially kind of in southern Asia. Yes, actually all over Asia and sort of Asian mainland. There is a small contribution from Denisovans, less than a percent, less than half a percent. But it's more varied than the Neanderthal contribution. So say in Oceania, there is up to five, six percent. The DNA of people there come from Denisovans. Wow. That's amazing. So so let me get this right.
5:27
So the picture is that, um, modern humans are migrating out of Africa and as they're migrating out, they encounter Neanderthals kind of in the European zone. And then, furthermore, as you're going toward the east, toward Asia, and that's where the Denisovans were, there's mixing there. So it's kind of a, you imagine, kind of a migration out of Africa, and then encountering these other populations and coexisting with them. Yeah, so that's a big picture.
5:56
We're in the process of sort of learning more about the details of this, how this happened. Find, for example, that the very earliest modern humans have come to Europe, sort of forty, forty five thousand years ago, seem to at least, some of those groups, mixed very a lot with Neanderthals. So we find that almost everyone is, there is a site in Bulgaria, for example, where we have three individuals from around forty five thousand years ago, modern humans, and they all have Neanderthals
6:29
in their family history in the last five, six, seven generations. But those very early modern humans that came hardly contributed anything to people today. So it's sort of later then, they come. So other modern humans that replace all these other forms, which eventually then leads to that the last thirty, forty thousand years of our history is actually unique, in that, there's only one form of humans around on the planet. We are alone, if you like, for the almost first time in our history.
7:04
People are not aware that Neanderthals were on Earth maybe four times longer than modern humans. They've been around for a very long time. They didn't leave much behind. So the key here then, is to work with ancient DNA. Is to work with DNA that's very, very old. It may be preserved in some non-ideal conditions, right? So we have, ancient DNA that you can find an amber. We have ancient DNA that's coming out from the permafrost is as multi permafrost kind of reveals
7:33
more and more, full specimens like, say, saber tooth tiger cubs, things like that. And then in your case,
7:42
ancient bone that's found in caves. So the process of extracting DNA from very old specimens, that was something you are very interested in when you were much younger. You're interested in Egyptology. You're interested in mummies. You had this idea of maybe the possibility of extracting DNA and analyzing DNA from mummies. Which sounds like it would just be almost impossible. So, I heard a story, I read a story where you practiced, by
8:10
purchasing a little bit of liver from the supermarket near the lab when you were a student, and taking it back to the lab and trying to, like, use that to maybe come up with a way to extract DNA from something that's dried and that's, you know, preserved. So, tell me a little bit about that liver experience. Well, sort of, I had studied Egyptology, actually at the university before I studied medicine and molecular biology. So I knew there were these thousands
8:39
and tens of thousands of mummies of animals and humans in, just, collections from Egypt around.
8:48
So, sort of it was a rather obvious thing to say. "Could we apply these new techniques of retrieving and cloning DNA to these remains"?
8:59
Well sort of most people thought that DNA was a very unstable molecule that would very rapidly, after death, be degraded. So that liver experiment was really to take a liver from, from the calf and dry it in such a way, sort of imitate mummification in ancient Egypt, and see if any DNA survived.
9:23
And there were sort of tweaks to that, it smelled pretty bad in the lab when I did it. But it turned out that, yes, DNA was preserved. It was degraded to shorter fragments, but it was indeed preserved. Which encouraged me to go on and try with mummies that are two or three thousand years old from Egypt. And then I actually retrieved some DNA from that. In hindsight, over the years, it had become pretty clear that that first DNA was for sure contaminations of present day people from myself
9:57
or museum curator or who it could have been. Right, I'd love to get into the idea of contamination, how prevalent that is in just a moment. But what was striking to me when I was reading your work about the mummies, was when you're working with the mummy samples, you wrote that it smells like warm baking bread as you're working at the samples. Why did it give off the smell of warm baking bread? Well, sort of, mummies tend to be brownish in color, right? The tissues and skin.
10:28
And part of that is from a chemical reaction between sugars and proteins and other things called a maillard reaction. That is actually the same reaction as when you bake bread and it becomes brown. So it sort of cross links between molecules. And this sort of smell then can come, you can even feel it when you, sort of say, drill in a mummy or so, it gets, warm. So you went from terrible smelling dry liver to like a nice bakery smell. Haha yeah. I'm sure you prefer the latter.
11:02
So going back to contamination, what was so fascinating is, the enormous puzzle, the difficulty of separating out, contaminating DNA from the DNA you want to study in the sample. So, um,
11:15
sometimes dust lands on the sample. The dust is often just dry skin. So you have human DNA, sort of like snowflakes kind of cascading down. You have people who handle the specimen, human beings have handled it. Some curators seem to even, like, lick the bone, to see, I don't know exactly why they're looking the bone, but you get saliva on there too. Yeah. So there's so many other channels. What other kinds of contaminants are present.
11:41
Like how else might the sample be contaminated with other DNA. Well so what I came to realize then over the first sort of decade, in a way, working with this, was that ancient DNA is sometimes preserved, but it's degraded to short fragments. And the vast majority of the DNA in old specimens or bones are from microorganisms that have colonized the bone, say, when it was in the ground for tens of thousands of years.
12:11
And then what is even more, if you studied human remains, would particularly then see here you'll see this, as you say, contamination of present day human DNA that can come, yes, from dust particles or chemicals you buy have tiny amounts of human DNA. Are the people who work in the factory that created the chemicals...? Yes. Yes. Right. So that is sort of a big, big issue that I have to deal with. We learned so with time that there are chemical modifications that accumulate
12:44
in DNA over thousands of years, as you preserve. And those modifications you can use as a sort of tag, to say this molecules that have these errors in them when I sequence them are actually old. So, it's sort of, there are ways around this. So today I think one can work pretty confidently and realize, when you have preserved genuine, authentic ancient DNA or not in a specimen. Yeah, so the Neanderthal specimens are so small and they're not very many of them.
13:19
So you don't, you don't want to waste the resources by practicing on them. So it's, it seemed like you, you and your team practice quote unquote on like cave bear specimens, other bone fragments from ancient, you know, the ancient past. Is that reasonable? Say that you're not only trying to learn more about the cave bear, but that also helped refine the protocol that you would then use on the Neanderthals. I mean, much of this was and is about improving the techniques,
13:52
and then working on animals is actually a lot easier than human remains, because, as you say, if you extract DNA from a cave bear and get sequences that are "bear like" but not identical to the present day bear, you're pretty sure you have the right thing. Whereas humans are much more difficult, actually, because it can often be difficult to distinguish a genuine DNA sequence from one that is from a present day person. Yeah, I wanted to ask you next about the caves in which these
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these specimens are found. But before there was something else that was very striking from your book, was that,
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and this was actually quite chilling for me to read, that seems like the Neanderthals were cannibals, because it seems like some of the specimens were byproducts of butchering and eating one another.
14:47
And in fact, because it was the byproduct of that food process, it seems to have better preserved the DNA, because you can maybe, like, maybe strip away the flesh and it dried quicker, than just a decomposing body would. That was fascinating because on the one hand, quite chilling, but then also enabled the research, made the research easier because the specimens were easier to work with and to extract DNA. Is that correct? Yes. I mean, there are
15:20
Neanderthal burials where you find the intact skeleton, but there are also many, many sites where the bones are crushed, as you say, and say bones that have bone marrow in them are crushed to get to the bone marrow and so on. You of course don't know why they did this. It could even be that you wanted to eat your relatives to incorporate them in, or it could be that you treated them more like meat. But the result of that, was that bones are in small fragments and probably lying
15:53
around on the surface and ,as you say, drying out fast, which limits amount of micro organisms that will, live in them, compared to when you bury a body in the ground.
16:08
So, obviously these are specimens discovered in caves. And it looks then like these caves were populated by living Neanderthals, early humans. Do you have a sense of just how long they may have been living in these caves? You know, was it multi generations? Was it thousands of years? I'm trying to get a picture of the cave and, sort of, that being sort of the Neanderthal equivalent of a city or small town, and that's where life happened.
16:37
Does it seem likely that they lived in caves for that long? Well, talking to archeologists who excavated these sites, I think there are both things that happened. There are sites that I think are more seasonal dwellings, perhaps that they followed animals and lived in certain periods there. And there are others that seem to have been much more continuous habitation. And many of these caves are excellent places to live. So there are Neanderthals who live there, and modern humans,
17:05
and even people in medieval times have lived in them. And we do find sort of family groups. You do find parents or offspring, for example, suggesting that one have lived for a longer time,
17:21
at a site. Yeah, I would imagine there could be a little bit of a tension between, some of the paleontologists and others who excavate the sites for, with whom you would have to do some coordination with, right? Because, I mean, you depend on the samples to do the genetic analysis.
17:39
And typically the paleontologists may have a different view of whether it's migration or, kind of like, multiple emergence of these early humans. And so there may be a little conflict, I would imagine, between, kind of, the way in which they envision the past, and what you're uncovering with the genetic research. Is there, in your view, a little bit of, like, tension? On the one hand, you need to sort of depend on them for the samples, but on the other hand,
18:09
your discoveries could be a little bit disruptive of the paradigms. I don't know, I mean, it is certainly an intimate collaboration. We rely on working together with paleontologists and archeologists to
18:25
get the samples. And then what we study is, of course, the genetic history of humans, right? There are, sort of, other things that we don't count approach. Sort of, count history, what technology did one use, was that transferred between groups, what did one hand and et cetera. So I think one complements each other much much more than that there is any kind of, conflict. There of course have been different theories in the past about the origin of modern humans.
19:02
We were sort of "stretched out of Africa" idea, where modern humans come out of Africa and replace everyone else without any mixture to other extreme use, modern human groups, continental groups, go back millions of years, essentially independent of each other. And of course, the genetic history turns out to be somewhere in between, right? Yes, the big picture is we come out of Africa, but there's also a contribution locally from these earlier groups that's existed.
19:36
There are some people who think that by genealogy, they imagine the family tree, you know,
19:43
relatives in the past and then, you know, reproduce and produce particular genomes. And so your entire genome has a genealogy. But something that you've written about, I thought was very fascinating, was actually each chromosome, in your genome, may have its separate genealogy, and each region of the chromosome may have its own genealogy. So in light of that, saying that we have a little bit of Neanderthal DNA or Denisovan DNA, makes more sense, in that reframing and what we mean by genealogy.
20:13
Could you speak a little bit more to that? Yes, of course, the case that, sort of, in each generation of chromosomes are broken up by recombination. So if I pass on one of my chromosomes, it's not an exact copy of my chromosome. It's sort of had parts of the two chromosomes I have inherited from my parents. And this means that, each region of the chromosome has its own history. So, for example, if you just walk along a chromosome in one part of it, say, I may be closer to a Neanderthal
20:46
than you are, and then bit further down the chromosome, you are closer to the Neanderthal than what I am, and so on. So we are a sort of mosaic of different genetic histories, if you like our genomes. So what we talk about when we say, say, the chimpanzee are our closest evolutionary living relative, and gorillas are a bit further away, is sort of the average across these histories. But it's still true that sort of for twenty, thirty percent of my genome, I'm closer to a gorilla,
21:18
but for the majority of it, I'm closer to a chimpanzee. So that is sort of
21:24
something we shouldn't lose track of, that it is sort of a mosaic of different histories. That's fascinating. Right. So, people may be tempted to think about your DNA as almost, almost like an analog thing, but it's really kind of digital that these little components that are being swapped out. So I want, I want to ask some more about the Denisovans, but let me just stay on the Neanderthals a little bit longer. So, Neanderthals have been around for quite a while.
21:52
What do we know, and what do we not know about them? So, it sounds like, and this is of obviously other areas of research outside of your area, but we have this picture of Neanderthals as being very simple, kind of crude, brutish, right? Maybe very powerful. There's this whole kind of cultural ethos around it. Where did that come from? Where did we get that idea about the Neanderthals? I don't really know. I think it's more historians of science that really study that.
22:25
I mean, yes, it is sort of a tendency to regard or sort of present day humans and maybe Europeans went on to discover Neanderthals. That's sort of the crown of human evolution and everything else as somehow brutish, right? Inferior, of course, in some sense, one could say Neanderthals were more successful than we are, because they survived much longer than we have so far. At least when we don't know what the future holds.
22:58
But it's also true, for example, that what came in modern humans like time is of a rapid cultural evolution, much, much more rapid than what the Neanderthals ever did. And that modern humans did a lot of things that other forms of humans did not do. I often am struck by the fact that over the last fifty thousand years, humans crossed water where you don't see land on the other side, and that's not a few times, they came to every little island
23:31
in the Pacific, something that these other forms never did, for example. That probably has to do with technology, but it also have to do with some kind of an attitude to life and your environment that's different. So you're saying that, when modern humans came to a large body of water, they were curious, it seems, to want to know what was on the other side, and they would cross that, but the Neanderthals would stop. They wouldn't cross. Yes. So sometimes I say modern humans are sort of crazy
24:01
and Neanderthals who are not.
24:04
I mean, you have to be crazy, I think, to sail out on the Pacific Ocean not knowing if anything is out there. And we don't seem to be able to stop all we have to go to Mars. And no one can really explain to me why you have to do it. There's no stopping. So there wouldn't be Neanderthal astronauts? Yeah. Do you think they had any kind of culture? Absolutely, yes. Yeah. How would you describe that? Oh, I'm not an expert on this, but they clearly, you know, had typical
24:35
stone tools that they produce that you find, et cetera. They had no fire, et cetera, for hunting cooperatively et cetera. Right. I think it was a paper published a few months ago, that suggested that
24:53
there are some arrowheads that were found that were produced about eighty thousand years ago in a region of Uzbekistan that was heavily populated at that time by Neanderthals. And they're surmising whether this could possibly be created by Neanderthals. So the tips were too small to do anything other than to be on the end of some kind of projectile shaft, suggesting an arrow.
25:16
And so it just left the researchers scratching their heads. Well, the timelines don't match up about who was in that area? And when they date these, what look like arrowheads, they look like are these Neanderthals arrowheads?
25:28
So that really got me fascinated. That's interesting. Maybe the Neanderthals are a little bit more clever than we give them credit. Yes, someone had these figures in Europe for four hundred thousand years, that are very sophisticated. They dated these eighty thousand years. Yeah. It wasn't published in plus one. Yeah. Yeah. That is interesting if that holds up because often we think that sort of bow and arrow comes with modern humans. Right. Right. So let me ask you about the Denisovans.
25:57
As you were getting ready to publish the whole genome sequence, in 2010, somebody called you and said, we have this finger bone, a little tiny bit of a finger, and I think it was one of your colleagues had discovered the mitochondrial DNA of that was neither human nor Neanderthal. We had actually sequenced the mitochondrial DNA of that. Yes. Yeah, yeah, yeah. Yes, yes. And that turned out to be quite different, this being outside Neanderthals and modern humans. Yeah. Yeah.
26:28
So, let's speak a little bit about, mitochondrial DNA sequencing that versus nuclear DNA. So mitochondria are the powerhouses of the human cell. They're inherited from the maternal line from mothers. It's passed on to the egg, the sperm doesn't really have that and that moves onto the babies. So you can sort of, you can trace maternal lineage and maybe migration that way. And that was your first work with the mitochondrial Neanderthal genome.
26:56
So that was what was sequenced, and then what you really were interested in, is could we possibly sequence nuclear genome of the, Denisovan. So tell me about that work, and was that difficult to do to move to that. Yeah, I mean the mitochondria has the advantage that there are many, many copies per send. So it's sort of easier to retrieve from badly degraded small amounts of DNA. But, as you say, it sort of represents just one side of history. The female side.
27:24
And it's also one unit that isn't this mosaic where you have an average of many histories. So there's a lot of stochasticity of just chance that comes into play there. So that's why sort of the mitochondria, yes it's interesting, but it's really not the full story of the genetic history of the group.
27:46
So for the Denisovans are a great example of that. So when we sequence the mitochondrial genome first, we thought we had something like Homo erectus or so because the common ancestor with the mitochondria went back like a million years, very deep. Whereas present day human mitochondria and Neanderthal mitochondria go back half a million years or so. So we thought it was something outside. And then when we got the nuclear genome, we realized that actually that in this,
28:17
sort of sister group of Neanderthals, and modern humans are outside of them. That is sort of the true story of what has happened.
28:28
Do we have an idea of what they look like? I think recently they've been uncovering skulls. Yes, very recently there is a skull from Harbin in China, where one was able to retrieve mitochondrial DNA and show that it is Denisovan. And it's sort of yes, they have very big teeth and are quite robust. And there are actually a number of other sites in China that have things that look morphologically related to this. So Neanderthals, Denisovans were clearly sort of widespread in Asia. Yeah.
29:04
So the samples she worked with, for the Denisovan DNA, there was it was a finger about very, very small fragment of what's thought to be a child, a female child's finger bone, tip of the pinky, and then another Denisovans molar, and the molar tooth you wrote it looked like it was like fifty percent bigger than your molar. So that's, you mentioned large teeth, that's a large tooth. Yeah. So, I want to ask you about about the mixing of both modern human and Neanderthal and also the Denisovan.
29:36
And by the way, let me ask you, I mean, we in everyday life refer, use the word human to refer to us, what we call "modern humans". But in your line of work, you also call Neanderthals humans, right? And Denisovans humans. Can you tell me a little about how you use some of these terms? Because I think it's a little bit more, it's not quite what everyday people think of when they think of the word human. Well, so I mean, there's always this discussion. What were the Neanderthals and Denisovans?
30:05
Were they another species or what?
30:09
And I think in some sense I say that's a sort of very academic discussion that only some professors are interested in. Really. If we describe that, yes, Neanderthals and modern humans met or mixed with each other, and some of these children were successful and contributed to people today, that is an interesting story, and I would clearly call them human, since this happened. So we tend to say this was another form of human or another group of human or something like that.
30:43
I'm fascinated by that. I know that you seem not to be that interested in, was it mainly, Neanderthal men mating with human women or the other way around? I think some people are quite fascinated about it, because that might say something about sort of the social interaction of the two groups. But clearly, what was, so I'm raising it for the following reason. If at that time, as in many parts of the world today, women, females, are responsible for raising the offspring,
31:13
then if there was a Neanderthal man meeting with a modern human woman, then that child would have been raised in a human community. I think that's fascinating as opposed to maybe the other way around. So I think personally, you may not be so interested. You're more interested in the fact that the mixing happened, but whether it was mainly male to female or female to male, I think for some people, when they try to imagine the social life of that mixing could be...
31:40
I agree that if we can find out about socially how this happened, that would be fascinating.
31:48
I mean, it's clearly not just one way, I think. It could have been preferentially one way.
31:56
But there's no way for us of telling. They tend to become what I call "paleo-fantasy", where we project our sort of ideas back into the past, and it says more about ourselves and our proclivities than and what's really happened. It is people writing Svante Pääbo fanfiction about what's happening at that time.
32:20
Haha. Right, well, so if they if they were getting together, then were they sharing ideas? How are they able to communicate with one another? These are all questions that I think... I mean, there are evidence from archeology that Neanderthals seem to have picked up some modern human technology in these transitional industries, for Château de Péronne and in France, for example, and or several other, exactly industries. I do think there were also cultural interactions
32:51
and we will probably learn more about that over the next few years, because there's also this cool development where one is able to now often retrieve DNA from archeological sediments. So that one is not just limited to finding bones. That's right. So you could go sort of through the different layers where you find stone tools, for example, and see what humans were Neanderthals and modern humans that dated. And then much better associate ancient industries with what groups made them. Yeah.
33:28
And I think this sort of direction is going in the direction that, yes, one did exchange sort of cultural things also, and that Neanderthals were probably involved in doing some modern human technology. Yeah, that makes a lot of sense. It's almost like doing forensics, like what we do today on crime scenes and try to collect DNA from just the environment is were constantly shedding DNA into the environment. So tell me you've been to Denisova Cave. Tell me, what is that like?
34:01
I mean, so it must be a limestone cave, and that's favorable. Yes. It's sort of the limestone cave. And that is very favorable for preservation, because it makes the ph neutral, slightly basic. What's really bad for the preservation of DNA is acidic conditions because it sort of degrades the DNA. So, in fact, almost all caves where one has successfully retrieved DNA are limestone caves. And it's a fascinating site. It's a sort of three chambers, and the main chamber is really high.
34:36
And as there's crack up in the ceilings, it's sort of like almost a bit like a church. So the light comes down in a big shadow? Yes. And it's fascinating to realize that
34:48
Neanderthals have lived there, Denisovans have lived there, Modern humans have lived there at this place. So there must be so much to uncover in that site. Yes. And I mean, it's been excavated every year. There's work going on there from the, Russian archeologists. Wow. So this reminds me, then, of the early interest in just Egyptology and just other artifacts. I heard one time that when you were a child, you found a large shatter pot, like, a very old pot in some site, and you
35:24
actually piece it back together and did something quite large. And that's just a beautiful metaphor for me about just the work you've also done with DNA, and being able to reconstruct it. So so tell me what was this pot, and tell me about where you found it. So I think that it's sort of like many kids, I was fascinated by your sort of archeology and of finding old things, and my mom was very supportive of that. So one thing in Sweden that was there's
35:52
often sort of storms in the fall, with trees fall over. So you have these roots that sort of can sort of get that loss of the, of the, the soil. It just brings up the past when it falls. And so, she would drive me to places where we would be chanced to find something, and at that one place, we sort of found, I found pots from the Stone age. There, like four thousand, four thousand two hundred years old, and lots of these little shirts.
36:25
And one could actually fit them together to quite a big piece of, of a pot, which was absolutely fascinating to me. And sometimes you can even see imprint of fingers in them. That must have been so exciting. But I just thought that's just a wonderful metaphor, just kind of, again, that mindset of going back and retrieving items in the past and piecing together the history and finding kind of the DNA fingerprint. Haha DNA fingerprint, the DNA fingerprint
36:56
of the life that was around which you're looking at. I mean, you're not only just looking at physical specimens, but you're looking at something about people who existed, who were living in the midst of a cave or,
37:10
so I just, when I hear that story I just thought this is just so wonderful. There are people who think it's quite something that, you know, your discovery that we have, like the Neanderthal DNA lives among us today. And I think you've got some, like, contest and people saying things like, "Oh, you know, here's a picture of my husband and I think he must be part Neanderthal". And lots of people like, kind of, you know, in a way kind of proud that they may have Neanderthal. I mean, tell me
37:36
about the experience of people reaching out to you and saying and offering pictures and their stories. Yes. I mean, it's sort of, it was very early on. It started back in 2010 when we published this mixing and just started getting letters and emails from people
37:54
claiming that they know people who are Neanderthals. And there's this interesting pattern that sort of there are quite a lot of women who write that their men are Neanderthals and there's almost no men who claim their wives are Neanderthals. Which also says something about how we think about Neanderthals. And that it can almost, for men, be sort of a positive trait to be Neanderthal in our imagination, and not so much for women. Yeah. I told my kickboxing coach one time, he's a very big,
38:26
you know, man from Hungary. And I said, yeah, did you know that you may have some Neanderthal DNA? He was very happy to hear that. Well, that must make me a good fighter. Haha.
38:37
So let me ask you then, for the Denisovans, there's been some really rapid research on sort of the DNA found in existing people. And, there may be some health implications of that, also for the Neanderthals. There was a paper that was published recently, which suggests that about thirty three percent of Mexicans have this gene that is associated with Denisovans, and could be, protective against infection. So maybe as humans were migrating into South America,
39:13
that was competitively advantageous somehow for their survival. So can you speak more to like, other findings we're seeing about you know, presence of ancient DNA in humans, and how that might have some health effects on people today? Yes, I think one is learning more and more of that. There is both that there are genetic variants that one already knew about since decades that are medically important, that turn out to come from Neanderthals or from Denisovans.
39:42
So there are sort of a variant that you test clinically if you give blood thinners to people, if you have an artificial heart valve, for example, because with those variants, you have to give lower doses of your blood thinner so you don't have serious bleeding. And that variant that is a higher risk for bleeding comes from Neanderthals, for example.
40:03
And then, it's sort of also that one discovers now that things can become important that come from Neanderthals. But the most striking example to me was in the COVID pandemic, where there was the risk factors that we all know about: old age, male sex and so on. But there were also genetic risk factors. And there's one factor, on chromosome three, that doubles or triples your risk of becoming severely ill or even dying when you're infected with the SARS-CoV-2 virus.
40:37
And that risk variant comes from Neanderthals tt turns out. So it was, in a way fascinating to me that Neanderthals disappeared forty thousand years ago, but suddenly a contribution for them becomes very important when a new virus comes around.
40:54
And that results in then at least a million extra deaths in the pandemic, this variant. Yeah, there seems to be some more findings of maybe having Neanderthal DNA doesn't necessarily make you stronger or tougher, but may make you more vulnerable to certain things. Yeah. You also spoke about, like, the pain pathway, that maybe, that might be more sensitive. But in general, I think there's a message there. Say, for example, that thing that makes them more
41:24
at risk to become severely ill if you're infected with SARS-CoV-2, the very same variant, also down regulates protein, that is the receptor for HIV sort of virus. That gives us H CCR five. So if you have this variant, you're worse off. If you're infected by SARS-CoV-2, but you're actually better off if you're exposed to HIV because you're less likely to be infected, about twenty five percent less likely. And I think that illustrates that almost all genetic variants, it's really an interaction
41:58
with the environment in this case which virus you're exposed to. So variant is often good in one situation and and bad in another situation.
42:09
So yes, there is this sort of variant that counts on Neanderthals that makes you more sort of sensitive to pain. Yeah. So, and that can be bad obviously, but it can also be sort of a good thing to be more sensitive. sense more of when something's wrong in your body that affects a protein that people who have the total lack of that protein, it's actually very bad, you know, pain and your life expectancy is actually quite short, situation. Yeah. Going back to sort of, you know, people
42:43
feeling proud about having maybe some Neanderthal DNA. So there was a study that came out that showed that very, very few, a small percentage of East Asians that are lactose tolerant seem to have that gene from the Neanderthals. So, so I'm lactose tolerant. Yeah, yeah, I'm lactose tolerant, and I enjoy milk and ice cream and everything. And I like to thank my Neanderthal ancestor for that. So I guess, you know, in some respects,
43:11
yeah. People like me get excited about maybe the possible link to the past. So there are these tools now, CRISPR. There are stem cells that you can create from bio specimens. So the combination of creating cells from specimens,
43:29
so the possibility of creating cells from specimens that could be any kind of cell type and manipulating them genetically with CRSIPR. Is that, are those tools interesting to you and the kind of work you want to pursue? Absolutely. So my own group, we have actually evolved more into looking into the functional differences between Neanderthals and modern humans. One area we particularly interested in is, sort of, genetic changes that happened since the separate
43:56
from Neanderthals and Denisovans has spread to everyone today. So these are sort of changes then, that define us genetic, if you like, is modern humans. And one interesting question is, do any of them have sort of physiological consequences. And it's a dilemma, of course, to study something that everyone has today, because we cannot just take people who have it and not have it and compare them to each other. So then we will have to work in model systems.
44:26
And one really good one, is, let's just say, human stem cells, that you can then use CRISPR-Cas9 to add it back to the ancestral state that is also in Neanderthals. And then you can differentiate these cells, for example, to brain organoids, where we sort of induce the cells to make little sort of balls of tissue a few millimeters big that. Sort of mimic early stages in brain development. So for some such changes we have done that
44:57
and others have done that, to look at things that and found changes and in modern humans that, for example, influence how chromosomes segregate in or at least stem cells. And it seems that they segregate more accurately in the modern human state than an ancestral state, for example. Or there are changes there that seems to make for slightly more new groups being born. So Neanderthals, for example, have just as big brains as we have, but just
45:25
sort of an outstanding question that would be really fascinating to learn something about in the next five years or so, is if it's organized in the same way as, as our brains or all their subtle differences there. Recently I was a bioethics reviewer for a manuscript for Nature. And in the, methods section, they mentioned that they had used a chimpanzee IPS cell line, the "Sandra A" IPS cell line, I believe that you were behind the creation of that cell line, is that correct? Yeah.
45:55
Oh, why did you create that IPS line? And by the way, I mean, the way that you make an IPS cell line, it's noninvasive. You can just take some blood from the chimpanzee, reprogram the cells there into a stem cell, and then do all kinds of crazy things with that stem cell line. So it was noninvasive work. But why did you create the "Sandra A" line? Well, back in 2010, 2015 one direction of our work was to compare these brain organoids from humans,
46:22
chimpanzees, gorillas, orangutans to look sort of for differences, because that's to say you want to do these things in a noninvasive way. You sort of cannot use embryos of humans or this species to do this. So this is sort of almost the only approach to study brain development in a sort of ethical way. In your book, you mentioned that there was a time where you contemplated whether it would be prudent to, patent or have some kind of restrictions on how people could use a Neanderthal genome,
47:00
uh data.
47:02
Maybe there are some concerns about people kind of commercially kind of using that for some kind of ancestry testing and other things and uses that maybe you wouldn't really be super excited about. Whatever happened with that? It's not restricted in any way? So researcher can say, I want to get a stem cell line from human or chimpanzee and try to make it a Neanderthal line and make an embryo model or something for that. Yeah. This guy in my book had a big debate in
47:30
the group of sort of if we would sort of patent, and use of the patent, you can patent a genome, you can patent the use of it. If we would sort of patent the use of studying, say, your Neanderthal ancestry, because we realized it would probably be a big commercial thing to, to test these things. And some people were furiously against patenting it. You know, in groups of sort of we backed away and did not do that.
47:59
Of course it is now a big thing. There are many companies that provide these services.
48:06
Which is fine. I mean, I think it's a good, no issue with that, but there are sort of no patent limitations. Yeah yeah yeah. Yeah. I get frequently asked to be an ethics reviewer for some of these high profile journals. When they get a manuscript that are not really sure what to do with because legally it was permissible, but it makes people uncomfortable. So you can get stem cell lines from chimpanzee, from human. You can you can make these models really mix the stem cells together. So yeah.
48:37
So, you kind of see how did they compete, and you might learn something about human development versus other animals. So these mixture combination model systems are concerning to some people. And you can make an embryo model of human, but maybe you can even do an embryo model of chimpanzee or embryo model or something like a Neanderthal. What are your thoughts about some of these possibilities of, in the lab, creating these cell models that
49:03
seem to recapitulate early life? You are much more an expert and have thought more deeply about this than me probably. I mean, I feel comfortable with starting things as long as it's sort of very early stages in development. Which is really us, the ball of cells that make some neurons from stem cells, that is not an embryo that have different organs, sort of, could start, sort of, having, sort of, functions as we think of a fetus or so, but so, and I think in
49:40
the time I have left in science, I would not be able to do these things anyway, to go farther with this. But yeah. You must get this question a lot, you know, what do you think makes us uniquely human?
49:53
Uniquely human meaning of modern human? What makes us uniquely human? How would you answer that? Well, I don't know, but what I'm struck by, is
50:08
this thing we discussed earlier how technology and culture starts changing very rapidly in our modern humans, spread across the whole globe. And there is also good evidence that when we lived in bigger groups and were more numerous, And it may be, but now I'm speculating that this big, having bigger groups and more individuals, is behind much of this fast cultural development. That is just more chance for innovation and bigger groups and also bigger chance to transmit it to a next generation,
50:41
because groups don't go extinct so quickly. So it may be that, for example, at the end of the day, there may be something that seems trivial, such as something that makes us have
50:55
bigger groups and bigger social systems that is crucial. The question is then, "what is that propensity in us"? Can we get at that? Is there also biological component to that? That's not going to be a totally biological thing, but it may be some propensity model
51:15
being in bigger social systems. So what have you not discovered yet that you would love to discover? I mean, a total dream would be to understand at least some aspects of this: What made modern human history that, to my mind, is so special, compared to other human groups possible. So can you tell me what was it like to get the call from Stockholm? What went through your mind when that phone rang and they told you the news? Well, I think that I actually totally
51:47
didn't anticipate this because I had the feeling our work is maybe interesting to many people, but not really fits a categories of the Nobel Prizes. So I totally thought this was a joke. You thought it was a joke? I'm of course from Sweden, so I know many people in Sweden. There was someone speaking Swedish calling me, claiming that he was on the Nobel committee, and I thought, "Oh, yeah, yeah, sure. Tell me more, tell me more. And like, after thirty seconds, it started sounding too serious.
52:16
I started to realize this may not be a joke. I've heard that in that phone call, they ask you, "Do you accept"? Did they ask you that question? No, they did not really ask that.
52:28
Now, what's fascinating about your personal history, in Korea, some people believe that in order to really understand somebody, you have to go back at least two generations. I mean, your work shows that we may have to go back two hundred thousand years. But let me ask you a little bit about your family. So you were raised, you were a single child raised by your mother, and your father, you saw, not that often. But your father also won the Nobel Prize in Physiology or Medicine.
52:54
Yes. So did you have thoughts of your father when you got the phone call from Stockholm? Of course, after a while, it was struck me that it was strange that exactly forty years earlier, my father also got the Nobel Prize.
53:10
I do think that this really my mother influenced. I grew up, as a single child with my mom. Saw my father sometimes on Saturdays for a few hours. So I think the person that has really influenced me is my mom.
53:26
Maybe the only influence from my father is to realize that it's not so special to be a Nobel laureate.
53:33
So, I guess, how do your children feel? Do they feel any pressure? I told my son that he now has 40 years time to... That the clock is ticking now, right? But I don't think they feel that. No. Right, right. They just think it's not that special. Yes. How could it be special, when grandpa and dad ... ... especially when you're a teenager. Exactly. Yeah. Yeah. All the allure is gone now. Yes. Because it's something dad got. Yes.
54:00
Well thank you so much for sharing your time with us today, and telling us all about your experiences with your research. That was really fascinating. Thanks. It was fun.
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