 Hello, welcome Konnichiwa, or as we say in Okinawa, haitai. What an absolute pleasure it is to welcome you here this evening. We have a fabulous program planned, I know you are in for a real treat. My name is Heather Young, I am the very proud Vice President of Communications and Public Relations at OIST, the Okinawa Institute of Science and Technology. I am also your emcee this evening at this public lecture by 2022 Nobel Prize winner and OIST adjunct professor, Sventa Papo. Please silence your phone so that we can have your undivided attention for 90 minutes. First we will hear from OIST's former president, then our Nobel Laureate, and we will conclude with a question and answer period. This will be your chance to ask a Nobelist about what inspires him or where his research is heading from here. We have planned an evening of science and story, an evening that will inform and inspire. First, thank you very much to the University of Tokyo for sharing this beautiful auditorium with us. The President, Dr. Fujii, will be joining us for a few minutes and we are grateful. We also have with us honored guests, supporters, partners, collaborators, and friends. That's you. Thank you very much for joining us. Now without further ado, we will hear from Peter Groose who will provide some remarks and then introduce our guest of honor. Dr. Groose is an internationally-relaunded researcher in the fields of gene regulation and developmental biology. After being president of the Max Planck Society, he served as president of OIST for six years from 2017 until the end of last year. During his tenure at OIST, he was particularly focused on excellence in research and innovation. Today, Dr. Groose is OIST's special advisor for innovation. Please give him a warm welcome. Thank you, Heather. And Konban Wah and a warm welcome to all of you for today's special event. I'm Peter Groose from the Okinawa Institute for Science and Technology, or OIST, as it's called in brief. Thank you for joining us today here at Tokyo University. My gratitude also goes to the president, Tehruo Fuji, for providing this wonderful lecture hall for this event. It's a privilege to welcome Vice Minister Hiroshi Tava and his colleagues from the Cabinet Office and other ministries in the audience as well. We all here today to learn more about the work of Professor Swanta Bebo and the pioneering discoveries he and his team have made to uncover the evolutionary history of humankind. That work, as you all know, was recognized most recently by the award of the 2022 Nobel Prize for Medicine or Physiology, and such a pioneering discovery were made possible through decades of public funding of the basic research that Swanta Bebo is doing. It gives me great pleasure that I could help by contributing funding to his breakthrough research, first when I was a president of the Max Planck Society, and more recently as the president of OIST. The principle of giving funds is trust in creativity and ingenuity of our researchers to leave well-known shores and sail into the unknown. That's what basic research is all about. Basic research in general prepares humankind for the challenges of the future. It addresses the most fundamental questions such as, where do we come from? Where are we? Where are we going? Basic discoveries undoubtedly have lengthened the life expectancies, fed the world, and taught humanity about our planet and the universe. So if reversing climate change and curing disease are all possible, it is researchers who will uncover a way to do so. Bringing these researchers together and giving them the tools and money they need will be critical to the future of humanity. This is quite simply why investing in excellent scientific research is so important for the advancement of humanity. And research excellence is the driving force for everything we do at OIST and Tokyo University. Let's now turn our attention to the speaker of today. It gives me great pleasure to introduce a friend and colleague, Professor Svante Pabo. He dedicated his life to the past and through this helped to shape the future. His discoveries have paved the way for a new understanding of our evolutionary history and what makes us uniquely human. It was in 1856, or I'll say two, that workers at a quarry in the Neander Valley of Germany came across an unusual foci. Scientists have never seen anything like this, an oval shaped skull with a low receding forehead and prominent brow ridges above their eyes, along with the presence of thick strong bones. This was the first time that a new kind of human was identified. As exciting as the discovery of the Neanderthals was, it was somewhat disappointing that we could learn very little about them for over a century. This was until Svante Pabo and his team helped to develop the tools that could be used to examine them more closely and to unveil their genetic makeup. It is because of their work that we now have come to know quite a bit about our closest extinct relative. Svante Pabo is a pioneer in this field. After first studying Egyptology and then switching to medicine, he was already researching the DNA of Egyptian mummies as a doctoral student. During his research days in Zurich, London, and Berkeley, he deepened his knowledge about the molecular biological methods. In 1990, he was offered a chair at the Ludwig's Maximilians University in Munich. Subsequently, Pabo moved to the Max Planck Institute for evolutionary anthropology in Leipzig. As one of the founding directors, he contributed to the successful establishment of the Institute. His idea from a young age of using molecular genetics to look at historical knowledge from a completely different angle has stuck with him over the years. He studied the genomes of cave bears and mammoth, and finally in 1997 of Neanderthals for the first time. In the course of time, Pabo managed to overcome the numerous difficulties that such a project entails, especially contaminations coming from other organisms. And hence laid the basis of our understanding of the genetic differences between Neanderthals and Homo sapiens. Also, thanks to their discoveries, we now know that 40,000 years after the last member of Neanderthal walked on Earth, their traces continue to live in our DNA. With this discovery, Swante Pabo helped to establish an entirely new scientific discipline called paleogenomics, giving rise to the resources that are now used extensively by the scientific community to understand human evolution and migration. But Swante's ambition is greater. He wants to understand what makes us different from the Neanderthals, what makes us uniquely human. To this end, he has started to analyze the functional role of the differences in the DNA between Neanderthal and us. He uncovered, for example, mutations in a gene required for speech. And together with Rylan Thutner from another Max Planck Institute, he found that our brains grow bigger based on the genetic differences. He will also tell you in his speech about an impact of the Neanderthal genes in our genomes on responding to COVID infection. It is not surprising that his pioneering work has received widespread acclaim. And Swante Pabo has been the recipient of numerous awards, including the 2020 Japan Prize and the 2022 Nobel Prize in Physiology or Medicine. So please join me, giving a very warm welcome to Professor Swante Pabo, our speaker of today. So thank you very much and thank you for this opportunity to come here and describe some of our work to you. So what I wanted to start out by doing is then reminding you about something that I think you are all aware of, and that is that modern humans, the ancestors of everyone alive on the planet today, emerged in Africa. And rather recently, in the order of 200,000 years ago or so. And those modern humans then started spreading out of Africa less than 100,000 years ago, seriously around 70,000 years ago or so. And what interests us is then that at that time there were not only modern humans around on the planet. There were other forms of humans that existed in Africa and quite famously in western Eurasia, what we call Neanderthals. And other forms of now extinct humans in eastern Eurasia that we're just beginning to learn more about. And our group is then obsessed with Neanderthals, if you like, since over 20 years. And you may ask, why should we be interested in Neanderthals? So Neanderthals were these sort of robust forms of humans to the left on this picture, a reconstructed skeleton of a Neanderthal and to the right a modern human. And they appear around 400, 450,000 years ago in the fossil record in western Eurasia. And they exist there until about 40,000 years ago when they disappeared in connection with that modern humans to the right appear. And to me, there are at least two reasons to be interested in Neanderthals. One is that they are the closest evolutionary relative to everyone alive today. So if we want to define ourselves from a biological or genetic perspective as a group, it's Neanderthals we should compare ourselves to and say, in what ways are we similar to them, in what ways are we different from them? Another reason is that they were here quite recently, just say, 1,400 generations ago or so, there were Neanderthals around. So we may ask what happened when modern humans met them, how did we deal with each other, and so on. But to then do that from a genetic perspective, you need to retrieve DNA from bones that are at least 40,000 years old. And that's the work that goes back to the early 80s in Sweden, where we started by looking at tissue remains from what looks to be very well preserved remains of humans, ancient Egyptian mammoths that are 2,000, 3,000, 4,000 years old, and look, for example, like this. And what I then did was to look histologically, look in the microscope in tissues from such remains. And for example, in the skin here from that mummy you just looked at, you can see things that look like cell nuclei in the basal levels of the skin. And in the cell nucleus is of course where the DNA is stored. So you could then try to stain that with dyes that bind to DNA, and you could see that there seemed to be DNA preserved in here. At about that time, Alan Wilson, who was a famous evolutionary biologist at UC Berkeley, published the first DNA sequences from a quagga, an extinct form of a zebra that's around 100 years old, that of course was a great encouragement to me too. So I went on and extracted DNA from that mummy, found human DNA sequences there, and published it to great fanfare at the time. However, in the following years, then it became clear that those DNA sequences that I had retrieved from the mummy was almost certainly or surely not from the mummy itself. They came from me or from some museum curator or archaeologist who had handled the specimens. Because what turned out then in subsequent years was that the DNA that is preserved in ancient remains like that is degraded to really short pieces compared to contemporary DNA. It's also chemically modified, and it exists in a vast excess of mitralial DNA from thonguses and bacteria that colonized plethora over thousands of years. And as a result of this, even tiny amounts of contaminating present-day DNA that won't show up at all when you study modern DNA can totally overwhelm the experiments when you work with these ancient remains. So what follows was then several years of sort of working to overcome these technical problems, avoiding contamination by various means, working under clean room conditions, using UV light to destroy DNA and bleach, etc. And if you did all that, you could indeed retrieve short fragments of what was endogenous DNA. And much of that work was then done with extinct animals because it was much easier to distinguish endogenous DNA from contaminating DNA that often comes from humans. So giant ground sloth, mammoths, and many other species like that. But our big interest was of course human evolution and particularly them neanderthals. And when we then, after about 15 years of sort of technical issues, started approaching neanderthals, there were two ideas around about how neanderthals were related to present-day people. One would be that modern humans come out of Africa, say 70,000 years ago, and replace neanderthals in Europe and other forms in Asia without any mixing, without any contribution from them to people today. And another idea would then be that modern humans come from Africa, mix with these forms, so there is some continuity from neanderthals, say, to present-day people in Western Eurasia. And you could of course imagine any sort of grade of this from total replacement, zero-percent contribution here to total continuity that some people believe in that, say, Europeans today are modern-day neanderthals. So we were very lucky then to get access to samples from not just any neanderthal, but the type specimen that was found in Neanderthal in 1856 and gave its name to this group of form of humans. Got a sample from the left upper humerus there, and worked with the technology at the time with the polymerase chain reaction to retrieve a part of the mitochondrial genome, which occurs in many copies per cell, so it's particularly likely to survive over a long time, and it's also particularly valuable, but it's inherited maternally, so you just look at the female side of history, if you like. Quite cumbersome, it was then retrieved, short pieces, cloned them, and believed the substitutions that were consistently there, and could reconstruct a tree of how this mitochondrial DNA was related to the mitochondrial DNA of people living today. And what you find, which was already known, was that the common ancestor of all mitochondrial genomes that exist today go back to an ancestor between 100, 200,000 years ago, and the common ancestor shared with the Neanderthal mitochondrial DNA and went back over half a million years. So it was very different from any mitochondrial DNA that people carry today. So in terms of the mitochondrial genome, it was then total replacement. But it was also of course clear already at the time that the full history is not found in this tiny little part of the genome, in the mitochondria, but in the nuclear genome, where the vast amounts of information, the majority of the information is contained. And the chance to then study the nuclear genome came at the beginning of the millennium with new sequencing techniques that came around. High throughput DNA sequences that allows you to inexpensively and efficiently sequence millions and billions of DNA molecules. So you could imagine just extracting the DNA and not trying to retrieve any particular part of it, but just sequencing all the DNA you have in there and start comparing it with the human genome that became available at the time. It was important to try to find good specimens, of course, when we looked at many different sites and found particularly one site in Southern Europe, this beautiful cave in Croatia, this bone here, and worked a lot on how you efficiently extract degraded DNA and manipulate it to be able to study it with such sequencing technology. It got a lot better with that. The sequencing machines got a lot more efficient too. And you could then indeed show that the fragment size that you could retrieve, a very short 20, 30, 40 nucleotides. When we now looked at these fragments, we could also begin to look at the very ends of them. And we then discovered something striking there that was that we had a lot of apparent C2T substitutions at the ends of the molecules, sometimes up to 50, 60% of all the C's appears at T's. And one could show that that is due to deamination of cytosines, so they become uracils. They lose this amino group here. And uracils and code for the DNA polymerase that you use for sequencing as T's. So you have artifacts in the form of C2T substitutions towards the end, that is a problem. You have to take it into account when you try to map these short fragments to the human genome. But it's also an advantage because they accumulate with time so you can sort of show that these molecules are indeed old. So you used three different bones, generated over a billion DNA molecules. And then developed programs to map them to the human genome. These short fragments taking these errors towards the ends into account was particularly are headed by informatics. Janet Kelso was instrumental in that. And you could then map it to the human genome and begin to ask questions when we had something like half the genome available in 2010. And the major question then was what about Neanderthals? Had they mixed with modern humans? Had they contributed to people today? And if they had done so, we would of course expect that in Europe whether they had existed Neanderthals, Europeans today should be closer to Neanderthals than people in Africa whether they had never been Neanderthals. So there was no reason to assume that Neanderthals would have contributed to Africans. So we asked that in different ways, but one very simple first way was to sequence five people from around the world, from Africa, Europe and Asia. And we actually put together a consortium of population geneticists that's helped us do these analysis, particularly David Reich at the Broad Institute and Monty Slatkin at UC Berkeley. And asked a rather simple question. So if they say if we have two present-day human genomes and we begin with taking two Africans, if we now assume that none of them is closer to Neanderthals, and this of course since Neanderthals have never been in Africa, as I said, there's no reason to assume that one African would be closer to the Neanderthals than another African. If you just looked at positions in the genome where these two Africans differ and then look at the Neanderthals and say, how often does this African match the Neanderthals, match the Neanderthals, how often does that one match the Neanderthals, it should be 50-50, right? They should be equally distant from the Neanderthals. And statistically speaking, that's also the case. If we then take a European individual and an African individual, what we found to my big surprise at the time was that we had more matching to the European individual, suggesting that there had been a contribution, genetic contribution from Neanderthals to present-day Europeans. What was even more surprising to me was that when we took a person from East Asia, from China, and do the same analysis, we again see more matching to the Neanderthals, although there have never been Neanderthals in China. And if we look in, say, Papua New Guinea, where for sure there had never been Neanderthals, we again see more matching. So with this analysis and other analysis, the idea that came out of that was that when modern humans left Africa, they presumably passed early on the Middle East, where there were Neanderthals at the time. And if these early modern humans that came out of Africa mixed with Neanderthals, they could then carry with them this genetic contribution, if you like, out to the rest of the world, also to part of the world where Neanderthals had not existed. And as a result of that, then, if your genetic roots are outside Africa, something like one or 2% of your genome comes from Neanderthals. What has then happened since then was that the goal was, of course, to get high-quality, good Neanderthal genomes that was particularly helped by sites in southern Siberia, for example, the Nisevac cave here, where Russian archaeologists under Anatoliy Derebianko excavate every year, and say a specimen like this, a toe bone of a Neanderthal. There were developments of technology, for example, an important advance was another way to make these DNA libraries that you can sequence, where you actually separate the two DNA strands and make libraries from single strands that you then fill in so that each double-stranded molecule had two chances to end up in the libraries, which was one sort of crucial advance that came around. So we could go from this bad genome here, where just about half of the genome is covered to something where every position on average is covered 30 times or more, so the quality is similar to genome you would sequence from a present-day person today. At the moment in the public domain, we have three high-quality Neanderthal genomes like that, that differ in age between about 50,000 years ago and 120,000 years ago, and we have a number of other ones on the way. So what you could then find when you compare these genomes to present-day people, and this is just illustrated with one chromosome here, so each line is one individual, and in red are fragments similar or identical to the Neanderthal genome. So you can see that among the other things here, there are fragments in every individual that come from Neanderthals, but you also see that different individuals carry different fragments. So, per person, it adds up to one or 2% of the genome, but you carry different fragments, so you can sort of, if you like, jump from individual to individual and ask how much can you puzzle together from different individuals today? And that adds up to be at least 40, 50% of the Neanderthal genome still exists today and walks around on two legs, if you like. What we also found early on was another bone from that site in Siberia, the Nisheva Cave, a tiny little bone that archeologists were very skilled at realizing that it might come from a human, turned out to be the last digit of a pinky of a child, and when we sequenced that genome to high quality, we were quite surprised to find that it was not a modern human, it was not a Neanderthal, but something else, quite distinct but related to Neanderthals that go back to common ancestors, ancestors something like 400,000 years back. So, we realized this was some new form of now extinct human that we had found. We decided to call them Denisovans after this site in Siberia, the Nisheva Cave, where they were found, just like Neanderthals are called Neanderthals after the first site where they were first found in Germany. We could ask if these Denisovans had also contributed to present day people, and indeed they have. We find no contribution in Europe and Western Asia, but we find a contribution in mainland Asia of much less than 1% in the order of perhaps 0.2% or so. Interestingly, in Oceania, in Papua New Guinea, Aboriginal Australians, up to 5% or 6% of the genome come from this now extinct Denisovans. And we can also begin to see some of the population structure of the Nisovans in present day people. So this is an analysis from Josh Ake's group at Princeton where you plot on this side how similar these fragments are to the Neanderthal genome, so you can see that there are the contribution here from the Neanderthals that is quite close to the genome we have sequenced. For the Nisovans, you can see that there is this contribution in Papua New Guinea that is quite distant from the genome that we have sequenced. Identity would be up here. If we now instead look in Japan, we find this contribution from Neanderthals similar to Papua New Guinea, we find this contribution from the Nisovans similar to that one, but in addition, another contribution from the Nisovans that's very close to the genome we sequenced. So in East Asia, for example, in Japan, there are at least two different distinct the Nisovan populations that have contributed to present day people. So if we summarize in the first part, what we think we know about the origin of Neanderthals, the Nisovans and modern humans from studying genomes, there is some origin of Neanderthals and Nisovans in Africa, some common origin of people that live Africa and become in Western Eurasia, what we call Neanderthals, in Eastern Eurasia, what we call the Nisovans. We don't know where the sort of border between these groups have been. We do know that in Southern Siberia and the Nisova Cave, that sometimes there has been Nisovans at other times Neanderthals, and we also know that sometimes they have mixed. Then there is an origin of modern humans in Africa. They come out, mix with Neanderthals early on, continue to spread and mix several times with Neanderthals. In the East, they mix with Nisovans also several times and then spread out to other parts of the world when modern humans had never been. And these other groups then disappear with time but live on in this contribution in present day people from Neanderthals and from the Nisovans. You may then ask our Africans, very different in that they don't have this contribution from earlier forms of humans in their genome. I think obviously the origin of modern humans were some place in Africa and they spread across the African continent too. If one mixed outside Africa with other forms, I think one surely did it also in Africa but we have no archaic genome, some extinct forms of humans in Africa yet. But when we get that, I'm pretty sure that the same thing will have gone on in Africa. An interesting thing in the last two years is that we're beginning to get very direct evidence of this mixing with Neanderthals. The first example of that comes from Romania. A site called Vasa Cave were cavers. Back in the 2011 found a human mandible that looks like a modern human mandible but when it was dated it was found to be at least 40,000 years old. So it's one of the earliest modern humans in Europe. So we're very interested in studying the genome to ask if that individual had already mixed with Neanderthals. And on the different chromosomes here, one to 22, we have marked in blue fragments similar to the Neanderthal genome. And you can see that indeed the ancestors of this individual have mixed with Neanderthals and you can also see that sometimes huge, huge segments of the chromosome come from Neanderthals, half the chromosome are there. And that of course indicates that this individual had close relatives in their family history that were Neanderthals. So you can then show that six, five, or four generations back, this individual here had a Neanderthal ancestor. And we're not sure how many generations because there is of course a lot of stochasticity or chance in how big your chunks of chromosomes do inherit from your ancestors. So there is now a second site in Bulgaria, but your hero where one finds technology typical of these early modern humans. You found three teeth of modern humans deep down in the stratigraphy about 45,000 years ago. So these are indeed probably the earliest modern humans we have in Europe. 10,000 years later there were also modern humans living in the cave. And when we now study the genomes of these individuals we find that the old ones all have a lot on the Neanderthal contribution. And you can see that they all had the Neanderthal relatives in their family history. If you look 10,000 years later in the same cave, people look pretty much like today having around 2% or so of their genome from Neanderthals. So the picture that is emerging is that the first modern humans that came out of Africa probably mixed quite extensively with resident Neanderthals. And a large part of the reason why Neanderthals disappeared and presumed in Denisovans too may be that they were simply assimilated into larger modern human populations that came because there are indications that modern humans were much more numerous than these archaic forms of humans. But what I then want to use the rest of the time here is discuss some examples of the influence today of this genetic contribution from Neanderthals and Denisovans to present day people. Because when we now have the genomes here we can start to look for genetic changes that happen here that are shared between modern humans and Neanderthals. Things that are unique to Neanderthals seen only in Neanderthals whereas humans look like the apes and find things where modern humans are different than Neanderthals look like the apes. And the first example I want to bring is change here something typical of Neanderthals and involves an iron channel. And much of this work is from Hugo Seberg that works in our institute in Germany and in Sweden. And he's particularly interested in ion channels. So he found that all the Neanderthal genomes we have in the encoded protein of this ion channel that free amino acid changes. And that's quite unique. It's the only protein we know that has three changes that are fixed among all Neanderthals. And this is an interesting ion channel. It sits in the peripheral nerve endings and are involved in initiating the sense of pain. So when we then express this ion channel that's involved in pain sensation, the Neanderthal version and the modern human version, we found that for a certain stimulation the Neanderthal version seem to let through more currents through the membrane as if it was sort of more sensitive. And I'm not sort of electrophysiologist but can show that that was due not to that it opened quicker the channel but that the inactivation was slower. It remained open longer after a certain stimulation. Could also show that that was due to two of these amino acid changes that sits intracellular and the third one didn't seem to influence this. We thought that this was unique to Neanderthals but what is also beginning to happen now is that I'm beginning to have large databases, biobanks or present-day people where you have genomic information and you have clinical information and questionnaires they have asked about their medical records and how they live their lives. And one of the easiest such biobank to access is a UK biobank in Britain and we found there to our surprise among the 260,000 individuals that 0.4% actually carry this Neanderthal version as a contribution from Neanderthals today. So this is not totally unique to Neanderthals. It has come over to some present-day people and you could then ask, look in the questionnaires these people have asked and pool all the questions that have to do with pain. How often you have headaches, stomach aches, back pains and so on and ask what it associates with. And for me it was the first time I could play with so large data sets. So of course something I was interested in what's the biggest correlate in your life with pain and sadly as you get older the biggest correlation is simply increasing age. The older you are the more pains and aches you have. It's trivial of course. It's because you have more medical problems older you get. More relevant for us was then that the individuals that carry this variant do report more pain in their lives than other people. And if you relate that to that age effect it is as if you were eight years older approximately. Approximately eight or nine years more of pain in your life if you like. Of course we cannot say because of that that the Neanderthals did experience more pain because we all know that the sense of pain is very much modulated in the spinal cord and particularly in the brain of course. But still it's interesting that people who carry one copy of this and this is so rare so everyone in the UK by your bank who has this is heterozygous, right? Neanderthals were homozygous for this change. So it may after all be so that may have to modify our view on Neanderthals a little bit. Maybe they were not the sort of insensitive brutes we think of but maybe they were actually wins. Another example I want to bring is has to do with the hormone progesterone that I think many of you are familiar with is produced from many places in the body but particularly from the corpus luteum and prepares the endometrium in the uterus for a possible pregnancy. And what we're interested in is the progesterone receptor to which the hormone binds. And it was already known that it existed a variant of the progesterone receptor that has this suspicious distribution in the world. Whenever you see a genetic variant that is absent or almost absent in Africa like this but exist outside Africa, it's almost certain that it comes from Neanderthals. And indeed it does. And this is sort of the well-known variant clinically because it's associated with preterm births. So we've premature babies which is cause of risk to the baby, especially in a society without medical care. So it had been speculated that this variant would sort of pose a selective disadvantage for Neanderthals. But something else that's beginning to happen now which is fascinating I think is that many groups in the world are generating genomes from modern humans of different ages. So if we sort of go over the last 15,000 years there are now thousands of genomes available particularly from Europe. So you can actually follow the frequency of the variant like this over time and see if it's decreased or increased or been stable. And if we now look in a little movie of this looking at in red or simply the archaic genomes carriers of this variant in present day in modern humans are black, non-carriers are gray. If we now move forward in time from 15,000 years ago towards present day you will find around 7,000 years ago or so that the frequency of this almost explodes. Which seems very strange. Why would a variant that cause you to have premature babies increase in frequency? So we looked again in the UK Biobank for this variant and we can now look here it's a modern human variant we look at the non Neanderthal variant and look what it is associated with in UK Biobank. And what you then find is that the modern variant is associated with bleeding early in pregnancy, is associated with miscarriages and is negatively associated with the number of sisters you have and also with brothers but not quite significantly so. So actually the modern variant increases the risk of losing the baby during pregnancy. So the situation seems to be that this Neanderthal variant is indeed associated with preterm births with early birth but is also protective against miscarriages and results in more live births. So it seems to be a trade-off with this Neanderthal variant sort of saves pregnancies that would otherwise be lost but the price you pay for that is that in some cases you have the early premature births. And we're beginning to understand the reason for that too. If you look at how much of the progesterone receptor is expressed from the Neanderthal variant relative to the modern variant you have a higher expression in the uterus for example in many tissues of this Neanderthal version. So you could imagine you have a bigger progesterone effect when you have more of the receptor. And indeed it's two studies that came out in 2020 that showed that if you give progesterone to women who has experienced previous miscarriages you can significantly increase the number of live births you have. Suggesting of course that you give more progesterone and more progesterone effect and with more receptor you may have the same effect. And this is a sort of a pattern that repeats itself that genetic variants that are often known clinically turn out to come from Neanderthals. Just one recent example would be the cytochrome P450 enzymes expressed in the liver that had to do with metabolism of many drugs and endogenous substances too of course. It turns out that they are closely related they come from Neanderthals, these variants of these and these variants are well known for example if you look at the half life of ibuprofen if you take that for pain it's about four times higher levels after taking these drugs because Neanderthal version is less efficient in degrading them. And more seriously if you take warfarin you have to give much lower doses if you have this Neanderthal variant here. So another area where these variants turn out to be important is in the current pandemic that we're still dealing with to some extent of course and as you know if you're infected by the SARS-CoV-2 virus many people have very few symptoms or even no symptoms at all but some people become very sick and even die. And we also know many of the risk factors of course old age, male sex, certain diseases and so on but all these risk factors are not enough to fully explain why some people become very ill and die and others hardly have any symptoms. So already early on there were attempts to look for genetic factors in the host and we were peripherally involved in a big international consortium that looked at that. And in the summer of 2020 the first results came in and it was really surprising to see that there was one big risk factor that dominated the risk of becoming severely ill on chromosome three and when we then looked at that risk factor we found that they came from Neanderthals. So whereas the protective variants are then modern if you like. So this variant had clearly come over from Neanderthals and exists in some people today. And for being a genetic risk factor it's quite a big one. So if in 2020 and beginning of 21 if you were hospitalized in Scandinavia and were not a carrier of this Neanderthal version you had about a 7% risk of dying if you came in with severe COVID to the intensive care. If you were a carrier you had about the 13 or 14% about the doubling of the risk. If you look at people over under the age of 60 with no other risk factors it's about a five times higher risk of dying which is in a way trivial if you eliminate other risk factors the genetic risk factors become a bigger factor. Unfortunate if you look in this region it's quite a complex region so it's not easy to see there are at least three genes whose expression is influenced by this region for all of them you can come up with sort of good speculations about how that may influence the severity of the disease but we and others are very interested of course in understanding the difference between this Neanderthal version and the modern version to perhaps understand why certain people become so sick because one might then be able to treat better. Interesting if you look around the world the frequency of this varies quite a lot. You could then overall estimate how many extra deaths you've had in the pandemic due to this Neanderthal contribution and unfortunately that's at least a million probably much more extra deaths you've had because of this. It's also quite interesting to note as you see on this slide here that in China and Japan in East Asia this variant is almost absent whereas it is very common in South Asia in India, Pakistan, Sri Lanka up to 50% of individuals are carriers. So this variant clearly had roles in the past where it has been eliminated by selection in this part of the world and it's been advantageous perhaps in other infectious diseases in South Asia. So this variant must have other functions and we're beginning to learn a little bit about that because who will see about it again? He noticed that if you look at this region on chromosome two where this risk variant sits here and look about a million base pairs downstream of this here, there is a gene there that some of you are familiar with I think, CCR5 which is a core receptor for HIV. So the virus that gives you AIDS. And if you then look at the expression of the CCR5 protein in individuals who carry the Neanderthal variant, it is lower. So this variant decreases expression of CCR5. And as you may know, if you have no CCR5, if you have a deletion on both chromosomes you're protected against HIV and cannot be infected. So indeed, if you then look at carriers of this Neanderthal risk variant for becoming severely ill in COVID, you can find that if you're exposed to the HIV virus you have about a 25% reduced risk of being infected. So this locus increases the risk for becoming severely ill in COVID but it decreases the risk to become infected with HIV. So it's just an example of what's really common genetic variants depending on the environment have can have positive and negative influences. It's at least double-edged sword and of course what has influenced the advent of this in East Asia versus South Asia or other factors. It's for sure a multi-edged sword if you like. Just before leaving the Neanderthals I would like to point out that they don't have only negative influence in the pandemic. As one now have more individuals you find sort of risk loci of smaller effect than this first one on chromosome three. One on chromosome 12, when we looked at that one it turns out that the Neanderthal version there is protected against severe disease. And in that case we understand mechanistically what's going on, there are three genes in there called OIS 1 to 3. There are enzymes that make this unusual little omega-nucleotide that activates a double-stranded RNA RNAs that degrades the viral genomes and it's turned out to be protective not only in this. And when you have more of this in the current pandemic but already in source code one pandemic like 15 years ago it's turned out to be protective. So to summarize that then unfortunately though the effect size on the risk locus from Neanderthals is quite a big one, doubling the risk overall and the decrease of risk from the chromosome 12 locus is only around 20%. Finally before ending I want to mention the type of changes that we're particularly interested in studying now. These are the changes that happen on the line to modern humans. So things that exist in all or almost everyone today but not existing in Neanderthals. And why are we so interested in those changes? I think that the reason is really that some of them may be involved in modern human specific features. And I do think that modern humans are special relative to Neanderthals and the Nisavans. When modern humans come around at least from 70,000 years ago or so technologies start changing rapidly. The Neanderthals technology at the beginning of their history and the end of their history 350,000 years later are quite similar at least to me as a non-expert I need an expert to explain to me how these things are different but I need no expert to explain to me that modern human technology 100,000 years ago is different from today. You also see that technology we can regionalize become very different say in Central Asia or in Europe and so on when modern humans come. What also counts in modern humans is figurative art. Art really depicts something that we immediately recognize what it is. And modern humans as they already mentioned become very numerous, go from being a few hundred thousand to millions of people and eventually billions of people spreading across open water colonizing all parts of the planet where humans can live. So we are very interested in those changes if some of them could be involved in this special behavior of modern humans. You can of course now list them and there are not that many around 30,000 changes or so. And we have begun to focus particularly on the most beginning with the most simple changes that changes amino acids in protein. And I just want to give you one example of that work. It involves an enzyme, glutathione reductase that has an amino acid change that is unique to modern humans and not seen in the under talks of the Niswems. This is an enzyme that's quite important. It's involved in reducing glutathione that becomes oxidized by free radicals, oxidizing radicals in the cells that will damage proteins and nucleic acids in the cell. So it reduces glutathione in every cycle here. But paradoxically in the absence of oxidative radicals and oxidized glutathione, this enzyme produces oxidative radicals actually. So it's sort of leaky. And again, when we express the Neanderthal version and the modern version and study it in vitro, you find that the Neanderthal version is more leaky, produces more free radicals in the absence of oxidized glutathione. So because then what we then looked again among modern humans, and indeed we can find this Neanderthal version in a very low proportion of present day people, but enough so that we can study its effects. And one finds that the Neanderthal version is associated with diseases that have a sort of inflammatory component that could be caused by these extra oxidative radicals with arteriosclerosis, inflammatory bowel disease and so on. So to end, I then hope I have convinced you that it can be interesting to have access to the genomes of our closest relatives because we can identify changes that are unique to modern humans and study those. Can identify Neanderthal specific variants and we can look at the contribution of Neanderthals and the Nisvans to present day people. And the way we do that is then to look in biobanks becoming increasingly important, I think it'll be very exciting here in Japan to work with biobanks to look at contributions also from the Nisvans that we know very little about at the moment. What you can also do is of course to engineer these ancestral variants into human stem cells for example and study the effects and even humanized or Neanderthalized model organisms. And this is then work that goes on in Germany and at the Max Planck Institute in Leipzig with people there but also since a few years in Okinawa Institute of Science and Technology where we have a small group that focuses on these modern human specific changes and model systems to study them in the excellent environment there with lots of groups that can help us particularly when neurobiology and other aspects of this. So with that I then thank you for your attention and glad to take questions. Wow, Professor, wow, thank you. I have a feeling that you have inspired as many questions as you have answered. To our guests, please make your way to one of the three microphones. There are two on this floor, one right here, another one stage left and on the second floor right in the center. There are a few host rules. Please take your interpretation receiver with you so that you can listen at the same time. Please keep your question to just one so as many people as possible may have the opportunity and please keep your questions on topic. So go ahead, line up now, please don't be shy. While folks are moving around, I will go first with a few of my questions. Professor Pebo, what was your immediate reaction when you heard the Nobel news? I think my immediate reaction was that it was probably a joke. A joke? I know quite a lot of people in Sweden. Someone who spoke Swedish and claimed that they came from the committee and I thought someone was trying to pull my leg. Okay, and how did your lab react because I saw an Instagram that you went for a swim? Yes, that's true. There is a tradition in our, we have a pond in our institute in the yard and there's a tradition that when you pass your PhD exam you're thrown into the pond and I think my students thought that I had passed the exam now so they throw me into the pond. That was proof. Okay, and mask, what drew you to OIST, to Okinawa, Japan, other than the warm people and the even warmer weather? I think the warm collegiality, maybe. It's a really dynamic institution. It's a young institution, just a little over 10 years. And it's sort of done away with a lot of rigid structures of departments and things like that. So it's very interactive. There are very many good groups here, particularly in the area we need help with, such as neurobiology and such things. So it's a wonderful place to do research actually. Okay, thank you. And next, because I think we're all wondering, what does a Nobel laureate eat for breakfast? It depends. Okay, professor, can you please grab your earpiece? Just hold it nearby. I will do the same and we will go to our audience. So let's start right in front of me here. What's your name and what's your question, please? Hello, Jose Sanardi. Since I was the first to line up, two questions, please. Very short, the second one. So one looking into the past, one looking into the future. So first of all, professor Pebo, thank you very much for your inspiring research and presentation today. So the first question is, you showed the data of the genetic charge of Neanderthals and Denisovans, how they spread from Africa through Southeast Asia. My question is, what happened to the Americas? I'm especially interested in Central or South America. My understanding is that that was the last tip of the human migration was to Tierra del Fuego. So do you have any data? What is your perspective concerning that that the first question? So of course, America's only modern humans come to the New World. So something in the order of 20,000 years ago, modern humans come to North and South America and they're sort of a sample of the northeast durations. So these are cake forms of humans, Neanderthals and Denisovans that were never in America, never in Australia, never on Madagascar actually. It's only with sort of this moving across open water and moving sort of long distance that counts. What about the genetic charge of the population today in the Americas when you explained this one to 2%? Yes. That we have today, this was observed in the Americas? Yes, yes. So Native Americans are sort of a subset of the East Asians. Okay, thank you very much. Second one, look into the future. AI, I work in AI, right? Artificial intelligence. How could AI or is AI helping you already in your research? Or do you envision something? I'm sort of not an expert on this at all. I mean, I do believe and I think I see on the horizon that this can be very important. We just discussed last night actually about using machine learning AI approaches to try to map Neanderthal and Denisovan variants to things, to medical data such as MRI data, et cetera. So I do think it will have a big role to play. Thank you very much. Thank you. Okay, let's go up at the top, your name and your question please. Hello, thank you. My name is Takahito. Professor Pippo, thank you so much. My question will be relating to the previous question. Genetics of the Neanderthal, through the evolution and migration, what environmental factors have influenced genetic refinement of Neanderthal? Is that environment or temperature or what kind of factors have influenced or transformed genetics more stronger to resist against the environment? Thank you. Well, I think in a way I would say that the same factors have influenced Neanderthals and Denisovans that have influenced modern humans. I think we can see that there's sort of these earlier forms of humans that lived for hundreds of thousands of years in the environment in Eurasia had adapted to pathogens and other things there. And when modern humans appear from Africa, they mix with these groups and fish up variants that are actually positive in that environment. So one example is in Tibet, for example. About 80% of people today in Tibet carry a variant of a gene called epasone that allows you to live at high altitudes with a little oxygen in the air without some of the complications that other people have. So if other people move to high altitudes, you compensate by making a lot of red blood cells. But that is a problem, for example, with blood clots in pregnancy and so on. This is another way to adapt to that. That turns out to come from Denisovans. And there's also now evidence that Denisovans lived on the high plateau in Tibet. So that was clearly sort of environmental adaptation that was transmitted even to modern day humans. So I would say there are no other mysterious factors so going on there is sort of things that were sort of beneficial. Often infectious diseases, often things from the environment, right? Thank you. Thank you. Now we'll go over to my left, your name and your question, please. Hi, my name is Thao. I'm a neurology resident at the University of Tokyo Hospital. It's related to the last question. So right now we're all modern humans and not Denisovans. You mentioned that modern humans came in more numbers related than Denisovans and right now only one or two percent of Denisovans genes live up in the modern human society. So this might be a difficult question, but what do you think is the most contributing factor that it is not Denisovans are present right now than modern humans? Sorry, I didn't quite get... So what do you think is the most contributing factor is that it's not the other way around that Neanderthals live on to the present, but modern humans live on to the present? So what's it like more to do with pathogenic, like microscopic organisms or more to do with diseases like cancer or more to do with the environment such as... So what's the major factor why Neanderthals disappeared and then... Yes. If you like. Yes, yes. We don't know, I think. I think it's striking to me this observation that among I think there are now seven or eight early modern humans where we have genomic information that are so early that they lived at the time when the Neanderthals were around. And with one exception, they all have close family relatives that were Neanderthals. So to suggest to me that one actually mixed a lot in the initial contact. So that has sort of led us more to speculate in the direction that it was more or less in the assimilation of these other groups into more numerous modern human groups that came. After all, 2% if we imagine there were 50 times more modern humans than Neanderthals, that would end up to be 2% right on the genome. I think it's not that simple, but a big factor could simply be that. Otherwise I sometimes also try to weasel out of the question by saying how we speculate about this is sort of more says something about our view of humanity than what really happened. We could talk about saying it was obviously the first great genocide. Just look at how we behave today. But then you could point to the Middle East where the modern humans already 120,000 years ago and the last Neanderthals 60,000 years ago. So if you like that 60,000 years of peaceful coexistence and that in the Middle East, right? If we could just have that today. So you know, it's just speculation. Thank you very much. Let's go back over here, your name and your question please. Hi, I'm Natsumina Kano walking as a science communicator in the National Museum of Emerging Science and Innovation in Tokyo, Japan. And after you won the Nobel Prize, we've held a program discussing how the research about human evolution contributes our daily lives or our future or our happiness for these citizens. And then not only Japanese medias or Nobel committees or even you really emphasize how useful it is for medical researchers. I know it's very important parts of your research and it's reasonable because you won medical prize. But I want to ask you in different way or another aspect how your research contributes our daily lives or our happiness for whole citizens. Well, first of all, I sometimes say when I get questions like that, this is a prize for medicine or physiology. I think it's more a sort of physiology part of that if you like. And I would say that what we do is actually curiosity driven. It's not different from making an archeological excavation at a site to say who lived there, how did they live, what happened to those people. We make excavations in the genome and try to find out what happened in the past. It's curiosity driven. We are of course very happy if some applications or insights from that become important in medicine or in other ways. But it's sort of a culture endeavor if you like to find out what happened to our ancestors. Thank you. Thank you. Thank you so much. We'll go up to the center. Your name and your question please. Hello, I'm Wakami Yamamoto, a first year master course student in Tokyo. My question would be like from kids compared to others, but have you ever thought about creating, like using the genome you got? Have you ever thought about creating non-delta like something like stem cells or organs or something like that? Yes. If you don't need to think about ethical issues. Yes, yes. I mean, there are people, particularly George Church at Harvard who go around saying crazy things such as we should recreate neanderthals or mammoths or other extinct species. There are a lot of reasons why that is impossible. A first one would be ethical. We sort of don't create human beings for scientific curiosity. There are technical reasons why that is impossible. We cannot sort of, with the technologies that we have on the horizon, change tens of thousands of positions in the genome. There's also repetitive parts of the genome that we don't know from these extinct groups because these are short fragments of DNA. And if a sequence is repetitive, we don't know from which copy it comes. We will never fully know the genome. But the approach is a valid one, but it's sort of more an approach where you would change a particular position in the genome and those are experiments we actually do. Take a human stem cell, change it to become neanderthal like at one position and then in tissue culture ask what effects that have. So that is sort of an approach you do take. But it's sort of looking at only single positions and single events. Okay, thank you. Let's go to my left. Your name and your question, please. Good evening. I'm sorry, I'm not good at speaking English. So I will talk about in Japanese. Okay, no problem. I have this. Excuse me, then may I raise my question? Professor, in the middle you talked about that the ancient people when you look for the genes of the neanderthals and others you needed to find for the better quality of the genome. What defines the better quality of the genes? Is this newer? I'm sure that you had several sets of samples. If the technology advances and you might be able to access to the better samples but you wanted to get high quality genes and what is the definition of the better or betterness of the quality if you could elaborate on that, be appreciated. Okay, sorry, I was late in turning on this. But so the question is what's the criteria for a better genome to have a better? Ah, yes, yes. Correct. Better quality genes. What is the better quality genes? So when we talk about the better quality of the genome it simply means that we have been able to sequence each position many times over. So we have this little fragment and on average when we sort of call it a good genome every position has been hit 30 times at least. So on average 30 times meaning very few positions are not seen at all and in most positions we have enough fragments we can even distinguish the two versions that may exist one from the mother and one from the father, right? So simply a question of sort of coverage as we said. Thank you. Let's go to my right here please, your name and your question. Hi, my name is Suda. I just have one question regarding I guess an academic career in a very competitive and almost I guess limited career of academics. What kept you going and still keeps you going? Is that passion, is that love or is it curiosity or something else? Well, I think it's really in a way curiosity and the exciting social experience to work in a group of people interested in the same question and working together contributing different aspects of that. I think it's sort of that's what I would miss the most in my life would actually be the socialist even more the social excitement of working together with a group of interesting and cool and exciting people. All right, thank you so much. Thank you. Okay, let's go to the top. Your name and question please. My name is Humi Hiro Naokawa from the University of Tokyo and I'm a master degree student of the universe cosmology. And I want to ask about the diversity of hominine. So you have discovered the mixture of homo sapiens and hominé and deuterances. And the fact is that only one space homo sapiens remains now and do you think is the fact fortunate or unfortunate for human beings because diversity is very important thing to make this world wonderful but simultaneously diversity can be origins of dispute or discrimination or war. Well, it's striking I think that say until 40, 30,000 years ago there were almost always different forms of humans around on the planet. The last 30, 40,000 years it's unique in that we are alone. There's no other form of human around. And yes, I would have the same question as you have. Had Neanderthals and the Nishevan survived, how would we deal with that today? Would we experience even worse racism against them than what we experience among us today because they were in some respects really different? Or could we think differently and say if we had them here today, we would not just have one type of humans, we would have other forms of humans around that also use tools that also communicate that also are sophisticated. Maybe we should not have this very clear distinction that we so easily make between humans and animals today if we had more diversity among humans. I think both things are possible and it sort of reflects our view of humans, how we speculate about that. So I wouldn't dare say if it would be bad or good if they were still around us, I really don't know. Thank you. Thank you. To my left, please, your name and question. My name is Masako Takatsu, graduate student. I want to be a researcher who can do pioneering research like you. Do you have any advice or tips for keeping motivation for challenging big or long-term project you did? Because, yes. I do get those questions now, especially after this price, and it's very difficult for me. I think the advice I would give is to do the things you are really interested in and think are important because it's generally rather automatic. If you do what you enjoy, you're generally good at it. It's rare that you find something really enjoyable if you're bad at it, right? And at least you have a good time while you do it. And I think that is then enough. You have a good time, and if you're lucky, and a large part of this is just luck, you happen to work on something that turns out to be important and turns out to be appreciated by your peers. So just follow what you find interesting, I would say. Thank you very much. Your writing book encouraged me a lot. Thank you very much. Okay, just to clarify, thank you. Right here, your name and question, please. I'm nervous. Hello, my name is Shin-Taro Nakamura. I'm in the City Arts and the High School. So I'll tell you about you, and it's like when you get into the college, you plan to study anthropology or science history, but you decided to study about medicine. So this change sounds like really huge. And my question is, have you ever met some of the obstacles or difficulties to study my completed different subjects? Because for me, at least, the anthropology and the genetics seems like really isolated. So my question is, have you ever met some of the obstacles or yourself? How did you overcome the problems? Yeah, I think sort of my path was that I thought I wanted to do archeology and Egyptology. And this was a romantic idea about it from childhood. And then when I was confronted with the reality of this at the university, it didn't live up to my romantic ideas. So then I didn't know what to do, and I said, okay, I can study medicine. At least you get a job when you're done with that. And then I sort of did a PhD and found this connection, right? And I think maybe there's a little message in there that is important, I think, to have a university system where you can combine unexpected things, that you combine things you are interested in and not have a rigid system that in many countries they now start with the sort of, you should study this set of subjects to become this profession because you become locked in into something rather rigid and predetermined. So I don't know how it works at the University of Tokyo. I hope you can sort of combine courses of different sorts, even unusual combinations. Thank you. Okay. We'll go up top. Your name and question, please. Hi, Professor Pable. My name is Taki and I'm studying particle physics here at University of Tokyo. And my dream is to be the first person in the world to detect these particles called neutrinals. From collapsing stars called supernovae. And this is important because it will tell us how the heavy elements that we see on Earth and in our bodies were created in the universe. And even though physics and anthropology is quite a different field, I'm faced with a similar challenge that you were faced that the particle that I want to find is buried in a tremendous amount of background. And so I expect about a couple of events in the experiment that I work at, over thousands of contaminating backgrounds every day. So my question for you is, how are you able to have such an unwavering focus on this seemingly impossible task of reducing the backgrounds and finding the tiny ancient Neanderthal DNA from the remains? Yeah, it's hard. I mean, I think you try to go around the problem, right? When we realized that studying human remains was almost impossible because of the contamination, couldn't distinguish DNA from materials whoever had handled the instruments from the endogenous thing, we turned to working on say mammoths. Because if you're from a mammoth, get the DNA sequence that's elephant-like but not identical to an elephant, you're very sure you have the right thing. And then using mammoths and other extinct animals worked on the methods and technology to sort of solve the problem. And one part of that was, for example, this chemical modification in the end of the molecules that could show needed thousands of years to accumulate in appreciable amounts. So then one could eventually come back to the humans and say, we believe only there's molecules that have this chemical modification that you don't see in your natural DNA. So I think it's sort of a question, sometimes if possible, to go around the problem, trying to do something else to pave the way for where you really want to go. Maybe. I don't know if it's applicable in particle physics. Thank you. Excellent, thank you. On my left, your name and question, please. Thank you for your lecture today. My name is Chetana. I want to know about your childhood. What was your favorite book when, and also what did you usually play with? Sorry, once again. Can you repeat it again, please? What was your favorite book and what did you usually play with when you were a child? Oh, what was my favorite book and my, hmm, I think Winnie the Pooh. And I don't know what I played. I played very different things, you know. Rather early, I started to do little excavations and try to find old stuff in the ground. Thank you. Thank you. Okay, let's go down here. You're leaving questions. Hello, my name is Rin Konishi, and I have two questions. And my first question is, when you started learning physiology and medicine, did it changed your life? Yes, I think so in the sense that I really started studying medicine because I wanted to go into research. And then when I actually started seeing patients, I discovered that that was much more fulfilling for me than what I thought. So I had a big crisis saying, shall I become a normal doctor and treat patients? Or should I become a researcher? And then I said, I'll try to do a PhD and then I can always come back to the hospital. Thank you. And that's where it still is. I'm not back at the hospital yet. Thank you. And my last question is, in your childhood, what was your dream? Well, among the dreams was really being an archaeologist and finding exciting things. Thank you. Yeah. Thank you. Okay, up at the top, your name and question, please. Hello, my name is Teaser, and thank you so much for today. It was really inspiring and I'm so honored that I got opportunity to ask you a question like this. And I'm a high school student and I'm really interested in anthropology, especially cultural anthropology. And I'm planning to go for anthropology major from my college. And if you have any advice for students who wants to study anthropology or seem kind of figurant, I would like to hear that. It is so hard for me these questions about advice. I really, my own advice is really to follow your interest, as I said, to do what you think is important and interesting because then the end of the things follow from that. Not listening to old folks saying what you should do but follow your own interests. Thank you. Don't listen to me, listen to others. Let's go to my left, your name and question, please. Hello, thank you very much for your lecture. My name is Aoi Aoi Sasaki. I'm a first year Bachelor of Science student at the University of Melbourne, Australia. And I aspire to be a literature in the field of anatomy and neuroscience. But people always tell me that being a scientist is not easy, sorry, not easy. So this is probably going to be a general question, but my question is what is the biggest hardship you faced and how did you overcome it as a literature? Well, I would say that it's also very privileged existence to be a scientist because you can follow your interest. You can often organize your life and work very freely. If you want to sleep late in the mornings, you can work late in the evenings instead to compensate for that. When you work in the hospital, you have to be there at seven o'clock in the morning, otherwise you're in deep trouble. So I would say yes, it may be hard in some aspects but there are also great, great benefits to being a scientist. You may earn less money, but you have more freedom than in most other professions. So I don't know, it's a question of what you want to have out of your work life, I guess. Thank you. Let's go down here. Your name and your question. Hi, I'm Mariko, I have two questions. How are you today? I'm fine, a little nervous. And one question, what is life like in Okinawa? What is life like in Okinawa? It's very good. I'm not there as much as I would like to be, but it's a great place, especially if you like to do things in the water. If you like snorkeling, uberdiving, it's a wonderful place. Thank you. Thank you. Thank you. Okay. Up top, your name and question, please. Thank you for your good presentation. And I'm Kosei Sasaki, Tokyo University of Marine Science and Technology. I have two questions. One is in your experiment or research, you feel hard when you cannot get the result, you don't expect it. And how to change your feeling or I want you to know your method or a replacement? Oh, I think I'm just as frustrated as everybody else when you don't get the results you want. Often an unexpected result can of course be an inroad to some insight that you hadn't expected. What is really frustrating is when an experiment just totally failed for technical reasons. That is very frustrating, but yes. And the second is, what do you need a research environment? What? Ah, just a second. Oh, just a second. Okay, please go ahead. The research environment. What kind of research environment is ideal? Do you have any requests about the better ideal research environments that you look forward to? Well, so I guess a good research environment is one where you have colleagues around. That can give you input and compliment expertise you have. And that is also sort of open to collaboration where people work together and rather than competing with each other. That is important. Within the group I always try to sort of say that it's very important to have a culture where everyone dares contribute. Where you can bring even your ideas that may be stupid or totally wrong to the table because among those things can be things that are unexpected or so that really takes the thing forward. So an environment where you feel safe to even ask the stupid, naive questions would be important. Such are things that I would sort of come up in my mind. Excellent. Thank you very much. You guys asked difficult questions there. Thank you very much. I'm sorry, but we do need to wrap up there. For folks still standing, please make your way back to your seats. Uh-oh. Let me pose one last question, Professor. Could you tell us about an influential figure in your life and how they might have guided you? Well, I think I was a postdoc at Berkeley with Alan Wilson, the person I showed there. And he's of course behind very much of our current understanding of modern human origins and things like that. So he was certainly a person that influenced me a lot in science. You've mentioned having great colleagues around a few times. Thank you. Okay, well, thank you. And thank you all very much for joining us. Thank you, Professor, for choosing OIST and choosing Japan to host your lab. We are proud to call you one of our own. To everyone here, thank you for being fans of Professor Pavo, fans of OIST and fans of science. Oh. If you would like to purchase Professor Pavo's books, his publisher has them for sale just outside. Now, if you haven't been to OIST, you are officially invited to come visit us and say hello in beautiful Onesun. But until then, thank you for attending this public lecture by Sventa Pavo, 2022 Nobel Prize winner and adjunct professor at OIST. Good night.