Public Lecture by Prof. Svante Pääbo at University of Tokyo (2022 Nobel Laureate)

foreign what an absolute pleasure it is to welcome you here this evening we have a fabulous program planned I know you're in for a real treat my name is Heather young I am the very proud vice president of communications and public relations at oyst the Okinawa Institute of Science and Technology and I'm also your MC this evening at this public lecture by 2022 Nobel Prize winner and oyst Adjunct professor sveta Papo please silence your phone so that we can have your undivided attention for 90 minutes first we will hear from oyst'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 plan 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 Fuji 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 no without further Ado we will hear from Peter Grouse who will provide some remarks and then introduce our guest of honor Dr Grouse is an internationally renowned researcher in the fields of Gene regulation and developmental biology after being president of the Max Planck Society he served as president of oyst for six years from 2017 until the end of last year during his tenure at oyst he was particularly focused on excellence in research and Innovation today Dr Gross is oyst special advisor for Innovation please give him a warm welcome [Applause] foreign [Applause] welcome to all of you for today's special event I'm Peter Bruce from the Okinawa Institute for Science and Technology or oyster as it's called in brief thank you for joining us today here at the Tokyo University my gratitude also goes to the president Fuji for providing this wonderful lecture hall for this event it's a privilege to welcome Vice Minister Hiroshi tawa and his colleagues from the cabinet office and other Ministries in the audience as well we all hear today to learn more about the work of Professor swanta Babel 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 wanted people 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 oyst 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 scientific 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 worry 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 hoist 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 smanta pebble he dedicated his life to the past and through this help 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 unsay 2 that workers at a quarry in the neander valley of Germany came across an unusual fossil 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 Wars it was somewhat disappointing that we could learn very little about them for over a century this was until Santa Babu 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 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 people moved to Mark 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 people managed to overcome the numerous difficulties that such a project entails especially contaminations coming from other organisms and hence late the basis of our understanding of the genetic differences between the undertals and Homo sapiens also thanks to their discoveries we now know that forty thousand years after the last member of Neanderthal walked on Earth their traces continue to live in our DNA with this discovery suante pebo helped to establish an entirely new scientific discipline called paleo genomics giving rise to the resources that are now used extensively by the scientific Community to understand human evolution and migration but swanta'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 wheelandhutna 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 covet infection it is not surprising that his pioneering work has received widespread acclaim and Swan tepebo has been the recipients the recipient of numerous Awards including the 2020 Japan price and the 2022 Nobel Prize in physiology or medicine so please join me giving a very warm welcome to professors wanted people our speaker of today [Applause] 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're all aware of and that is that modern humans the ancestors so 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 starting started spreading Out of Africa less than a hundred thousand years ago seriously around 70 000 years ago or so and what interests us is them that at that time they 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 the undertals were this sort of robust forms of humans to the left on this picture of reconstructed skeleton of a neanderthal and to the right of 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 they similar to them in what ways are we different from them another reason is that they were here quite recently just say 1400 Generations ago or so there weren't 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 in work that goes back to the early 80s in Sweden where it started by looking at tissue remains from what looks to be very well preserved remains of humans ancient Egyptian mamas that are two three four thousand years old and look for example like this and what I then did was to look histologically look in a microscope in tissues from such remains and for example in the skin here from that name you just do that you can see things that look like cell nuclei in the basal levels of the skin and in a sand nucleus is of course where the DNA is stored 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 clagia 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 Fun 4 at the time however in the following years then it became clear that to those DNA sequences that I had retrieved from The Mummy was almost certainly or surely not from the Imam itself they came from me you were from a museum curator 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 microbial DNA from funguses and bacteria that colonized the tissues 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 folders was then several years of sort of working to overcome these technical problems avoiding contamination by various means working in a 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 made their other species like that but our big interest was of course human evolution and particularly them Neanderthals and when we dance 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 mixed in without any contribution from them to people today and another idea would then be that modern numerals come from Africa mixed with these forms so there is some continuity from neanderthals say to present-day people in Western Eurasia contribution here to Total continuity that some people believed in that say Europeans today or modern day Neanderthals so we were very lucky then to get access to samples from not just any neanderthold but the type specimen that was found in Neanderthal in 1856 and gave its name to this group of form of humans we've got a sample from the left upper humerus there and worked with the technology at the time with the polymerist chain reaction to retrieve as part of the mitochondrial genome which occurs in many copies per cell so the particularly likely to survive over a long time and it's also particularly valuable but is inherited maternally so you just look at the female side of History if you like quite cumbersome with and 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 mitochondria 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 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 but the vast amounts of information the majority of 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 you're 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 is born here and worked a lot on the how you efficiently extract degraded DNA and manipulated to be able to study it with such sequencing technology got a lot better with that the sequencing machines got a lot more efficient too and we 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 discover something striking there that was that we had a lot of apparent C to T substitutions at the ends of the molecules sometimes up to 50 60 percent of all the Seas appears at everyone 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 teas so you have artifacts in the forms of C to T 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 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 it was particularly or had a bioinformatics Janet Kelso who was instrumental in 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 a 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 where there had existed Neanderthals Europeans today should be closer to neanderthals than people in Africa where there had never been neanderthals so there was no reason to assume that neanderthals would have contributed to Africans so we ask that in different ways but one very simple first way was to sequenced five people from around the world from Africa Europe and Asia and we actually put together Consortium a population geneticist that's helped us do this analysis particularly David Rai he has a broad Institute and Monty slatkin at UC Berkeley and asked rather simple question see if they're saying if we have two present and human genomes and we begin with taking two Africans if you now assume that none of them is closer to a neanderthal 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 noun deposit another African just looked at positions in the genome where these two Africans differ and then look at the Neanderthals and say how often does this Africa Neanderthal match how often does that one match it should be 50 50 right they should be equally distant from the Neanderthal 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 their 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 they've never been neanderthals in China and if we look and say Papua New Guinea we're for sure there had never been there and the thoughts 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 this early modern humans that come 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 parts of the world when you're on the top had not existed and as a result of that then if your genetic roots are outside Africa something like one or two percent of your genome Capital Neanderthals what has then happened since then was that the government was supposed to get high quality good Neanderthal genomes that was particularly helped by sites in southern Siberia for example the nisava cave here where Russian archaeologists under anatolidere Bianca excavate every year and their specimen like this a toe bone of an neanderthal there were developments of technology for example an important Advance was another way to make these DNA libraries that you can still request 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 we asked about half of the ketones 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 are the number of other ones on the way so what you could then find when you compare these enorms to present-day people and this is just Illustrated with one chromosome here so each line is one individual and in red or fragments similar or identical to the Neanderthal genome so you can see that amounts that Europeans 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 two percent of your genome but you carry different fragments so you can sort of if you like jump from Individual to individual and say ask how much can you Castle together from different individuals today and that adds up to be at least 40 50 percent 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 Mississippi cave a tiny little bone that the archaeologists were very skilled at realizing that it might come come from a human turned out to be the last digit of a pinky of a child and when we sequence that you know 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 the Nissans after this site in Siberia denisovakai where they were found just like neanderthals I called neanderthals after the first sight where they were first found in in Germany we could ask if these denisimus had also contributed to present-day people and indeed they had we find no contribution in Europe and Western Asia but we find a contribution in Mainland a shelf and watch less than one percent in the order perhaps 0.2 percent or so interestingly innocence up to five or six percent of the you know come from this now extinct the Nissans and we can also begin to see some of the population structure of the Nissans in present-day people so this is an analysis from Josh aikis 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 neanderthals that is quite close to the genome we have sequenced for the Nissans 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 Nissans similar to that one but in addition another contribution from the Nissans that's very close to the genome we sequence so in East Asia for example in Japan there are at least two different distinct Tennessee populations that have contributed to present-day people so if you summarize and the first part what we think we know about the origin of Neanderthals the Nissans and modern humans from studying genomes there is an origin of neanderthos Internationals in Africa and common origin of people that leave Africa and different become in Western Eurasia what we call neanderthals in eastern Eurasia what we call the nisswans we don't know whether the sort of border between these groups have been we do know that in southern Siberia and the nasiva cave at some time there has been the Nissans 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 mixed with neanderthals early on continue to spread and mix several times with neanderthals in the East they mix with the Nissans also several times and then spread out to other parts of the world where modern humans had never been and these other groups and disappear with time but live on in this contribution and present-day people from neanderthals and from the Nissans you may then ask are Africans very different in that they don't have this contribution from earlier forms of humans in their Dino and I think obviously the already know 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 was surely did it also in Africa but we had no archaican on 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 few 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 was a 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 if you're very interested in studying the genome to ask if that individual had already mixed with Neanderthals and with the on the different chromosomes here 1 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 the undertose half a chromosome arm 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 only undertal ancestor and we're not sure how many generations because there is of course a lot of stochasticity of chance in how big Shanks or chromosomes do you inherit from your ancestors so there is now a second site in Bulgaria but your hero where one finds technology typically this early modern humans you found three T's of modern humus deep down in the stratigraphy about 45 000 years ago so these are indeed probably the earliest modern humans we have in Europe ten thousand years later there were also modern humans living in the cave and when we now started the genus of these individuals we find that the old ones all have a lot of Neanderthal contribution and you can see that they all had the undertale relatives in their family history if we look 10 000 years later in the same cave people look pretty much like today having around two percent or so of the Arduino 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 the distance too maybe that they were simply assimilated into larger modern human populations that came because there are indications that modern humans were much more numerous than this 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 the Nissans 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 share between modern humus and Neanderthals things that are unique to neanderthals seen only 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 on neanderthals and involves an iron Channel and much of this work is from Hugo sayerberg 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 or this ION channel that's three 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 when Neanderthal versions seem to let through more current through the membrane as if it was sort of more sensitive and I'm not a sort of electrophysiologist but can show that that was due not to that it opened quicker the channel but that it the inactivation was slower it remained open longer after a certain stimulation could also show that that was due to two release amino acid changes that sit intracellularly 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 as I'm beginning to have large data databases biobanks or present-day people where you have genomic information and you have clinical information and questionnaires they had asked about their medical records and how they live their lives and one of the easiest such biobanger excess is a UK biobank in Britain and we found there to our surprise among the 260 000 individuals that 0.4 percent actually carry this Neanderthal version as the 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 what have you 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 the older you get more relevant for us Hussein 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 UK buy your bank who has this is heterozygous right neanderthals were homozygous for this change so it's May after all be so that may have to modify our viewer neanderthals a little bit maybe they were not this sort of insensitive brutes we think of but maybe they were actually twins another example I want to bring is has to do with a hormone progesterone but I think many of you are familiar with it's 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 pre-term births so with 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 you 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 a variant like this over time and see if it's a 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 is or black non-carriers are gray if enough move forward in time from 15 000 years ago two words 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 the UK by a bank and what you then find is that the modern variant is associated with bleeding early in pregnancy It's 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 that seems to be a trade-off it's with this Neanderthal variants sort of saves pregnancy 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 versions you could imagine you have a bigger progesterone effect when you have more of the receptor and indeed it or two studies that came out in 2020 that show 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 with more progesterone and more progesterone receptor effect and we're more receptor you may have the same effects 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 there's one recent example would be recytochrome p450 enzymes expressed in the liver that had to do with with metabolism or 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 they are Neanderthal version it's less efficient in degrading them and more seriously if you take Warfarin you have to give a much lower doses if you have this Neanderthal variant here so another area where these variance 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 source code II 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 I 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 I looked at that and in the summer of 2020 the first results came in and it was really surprising to see that it was one big risk factor that dominated the risk of becoming severely ill on chromosome 3. and when we then looked at that risk factor we found that they came from Neanderthals so where the protective variants are then modern if you like so this variant have clearly come over from neanderthals and exists in some people today and for being a genetic risk factor is quite a big one so if in 2020 and beginning of 21 if you were hospitalized in Scandinavian were not a carrier of this Neanderthal version you had about a seven percent risk of dying if you came in with severe covid to the Intensive Care if you were a carrier you had about a 13 or 14 percent 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 unfortunately 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 when we look around the world the frequency of this varies quite a lot you could then overall estimate how many extra deaths you have had in the pandemic due to this Neanderthal contribution and unfortunately that's at least a million probably much more extra deaths you have 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 percent 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 we will see a bearing again he noticed that if you look at this region on chromosome 2 where this risk variance sits here and look about a million base pairs down three numbers here there is a gene there that some of you are familiar with I think ccr5 which is a co-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 protective against HIV and cannot be infected so indeed if you then look at carriers of this Neanderthal risk variant for becoming severely alien covid you can find that if you're exposed to the HIV virus you have about a 25 reduced risk of being infected so it this Locus and increases the risk for becoming severely ill in covid but it decreases the risk to become infected with HIV so just an example of what's really common that genetic variance depending on the environment have can have positive and negative influences at least double-edged sword and of course what has influenced the absence of this in East Asia versus South Asia or other factors is 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 a negative influence in the pandemic as we now have more individuals you find sort of risk loci of smaller effect than this first 100 chromosome three one on chromosome 12 when we looked at that one it turns out that the Neanderthal version there is protective against severe disease and in that case we understand mechanistically what's going on there are three genes in there called oys one two three there are enzymes that make this unusual little oligonucleotide that activates a double-stranded RNA rnas that degrades the viral genomes and it's turned out to be protective not only in this when you have more of this in in the current pandemic but already in source code one pandemic like 15 years ago this turned out to be protective so to summarize that then unfortunate is all 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 percent finally before ending I want to mention the type of changes that were particularly interested in starting now these are the changes that happen on the line to modern humans the 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 Nissans when modern humans come around at least from 70 000 years ago or so Technologies start changing rapidly they Neanderthal 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 hundred thousand years ago is different from today you also see the technology become regionalized become very different say in Central Asia or in in Europe and so on when more than humans come what also comes in modern humans is figurative art art really depicts something that we immediately recognize what it is and modern humans as they already mentioned became 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 or modern humans you can of course now list them and 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 in enzymes reductase that has an amino acid change that is then unique to modern humans and not seen in neanderthal denisence this is an enzyme that's quite important it's involved in reducing glutathione that becomes oxidized by three radicals oxygen radicals in the cells that will damage proteins and nucleic acids in the cell so it reduces glutathiones it can reach cycle here but paradoxically in the absence of oxidative radicals and oxidase glutathione this enzyme produces oxidative radicals actually so it's sort of leaky and at the end when we express the Neanderthal version and the modern version and started in vitro you find that the Neanderthal version is more linky produces more free radicals in the absence of oxidase glucathione so we could then what we then looked again among modern humans and indeed we can find this neonatal 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 this extra oxidative radicals with Autodesk sclerosis inflammatory bowel disease and so on convinced you that it can be interesting to have access to the he knows 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 the Neanderthals and the Nissans to present-day people and the way we do that is then to look in biobanks that becoming increasingly important I think it'll be very exciting here in Japan to work with biobanks to look at contributions also from The Nest events that we know very little about at the moment what you can also do is across to engineer this 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 with neurobiology and other aspects of this so with that I then thank you for your attention I'm glad to take questions [Applause] well 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 um Professor Pabo uh what was your immediate reaction when you heard the Nobel news and I think by immediate interaction reaction was that it was probably a joke a joke I know quite a lot of people in Sweden someone with a spoken spoke Swedish and claimed that they came from the committee and I thought someone was trying to pull my leg hacked 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 in the 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 exam now so they throw me into the pond okay and mask what Drew you to waste to Okinawa Japan other than the warm people and the even warmer weather I think the warm collegiality maybe and it's a really Dynamic institution it's a young institution just a little over 10 years and it sort of I will 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 there 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 um 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 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 Bebo thank you very much for your inspiring research and presentation today so the first question is you show the data of the genetic charge of Neanderthals denisovans how they spread from Africa through Southeast Asia my question is what happened to the Americas I'm especially interested in Central South America my understanding is that that was the last tip of the human migration was to Tierra El Fuego so have you do you have any data what is your perspective concerning that that's the first question well so of course America's only modern humans come to uh the new world so something in the order of twenty thousand years ago modern humans come to North and South America and they're sort of a sample of the East Northeast durations so so these archaic forms of humans neanderthals and the Nissans they were never in Americas never in Australia never in Madagascar actually it's only with sort of this moving across open water and moving sort of long distance that comes whatever the genetic charge of the population today in the in the Americas when you you explain this one to one to two percent yes that we have today this was observed in the Americas yes yes so Native Americans are sort of a subset of a East Asians okay thank you very much second one looking into the future AI I work in AI right artificial intelligence how cool they are is AI helping you already in your research or do you ambition something I'm sort of not an expert on this um 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 the nisive and variants to things to Medical Data such as MRI data Etc so I do think it's we'll 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 takihito Professor people thank you so much my question will be relating to the previous question genetic uh genetics of the neandotal through the evolution and migration what environmental factors have influenced genetic refinement opening undertale is that the environment or a temperature or what kind of factors have influenced or transformed genetics more stronger to register against the environment thank you well I think in a way I would say that the same factors have influenced neanderthals and the Nissans as 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 to these groups and fish up variants that are actually positive in that environment so one example is in Tibet for example about 80 percent of people today in Tibet carry a variant of a gene called that allows you to live at high altitudes where the little oxygen in the air without some of the complications that other people have so if other people move to high altitude to 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 the nissibans and there is also now evidence that the Nissans lived on the high plateau in Tibet that was clearly sort of environmental adaptation that was transmitted even to modern day humans so uh I would say there are no other mysterious factors that still going on there it's 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 soil 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 neonithals um you mentioned that um modern humans came in more numbers related than neanderthals and then right now only one or two percent of nettle genes live up in the modern Human Society so um it might be a difficult question but um what do you think is the most contributing factor that um it is not the unsoles are present right now then sorry I didn't quite yet um so um what do you think is the most contributing factor is that um it's not the other way around but the other thoughts live on to the present but modern humans live onto the prison so what's more to do with um pathogenic like microscopic organisms or more to do with like diseases like cancer or more to do with the environment such as so what's a major factor why neanderthals disappeared and then um yes if you like yes yes yeah well we don't know I think um I think it's striking to me this observation that among I think 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's a sort of leather us more to speculate in the direction that it was more or less an assimilation of these other groups into more numerous modern human groups that came after all two percent if we imagine there were 50 times more modern humans than neanderthals that would end up to be two percent right of the you know I think it's not that simple but a big factor could simply be that otherwise I sometimes also try to resell 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 yeah no side 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 in the last neanderthals sixty thousand years ago so if you like that sixty thousand years of peaceful coexistence and that in the Middle East right if you could just have that today so you know it's just speculation thank you very much okay let's go back over here your name and your question please hi I'm NATO minakano working 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 with citizens and then uh not only Japanese meteors or novel committees or even new Theory emphasized how useful it is for medical researches I know it's very important parts of your research and it's reasonable because you want medical prize but I want to ask you in different way or another aspects how your research or how your research contributes our daily lives or our happiness whole citizens well first of all I sometimes say when I get questions like that 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 archaeological 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 is 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 to the center renaming your question please hello I'm welcome to a master of first year Master course students 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 um have you ever thought about creating non Delta like something like stem cells or organ organs or something like that yes if you don't need to think about ethical issues yes yes I mean there are people particularly your church it's Harvard who go around saying crazy things such as we should create 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 decisions in the genome there's also repetitive parts of the genome that we don't know from these extinct groups because it's a short fragrance of DNA and if your 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 of 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 thank you let's go to my left your name and your question please excuse me then may I read my question talked about that the ancient people when you look for the genes of the neandertholds and others you needed to uh find for the better quality of the genome what defines the better quality of the genes is it 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 a high quality jeans and what is the definition of the better or betterness of the quality if you could elaborate on that be appreciated late in turning on this but so the question is what's what the criteria for a better genome to have a better absolutely solution correct better quality jeans what is the better quality jeans 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 these little fragments 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 the 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 it's simply a question of sort of coverage as we say excellent thank you let's go to my right here please your name in your question hi my name is Shira um 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 it love or is it curiosity or something else well I think it's really in a way curiosity and 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 is sort of that's what I would miss the most in my life it would actually be the Socialist even more the social excitement of working together with a group of interesting and cool and exciting people okay thank you so much thank you okay let's go to the top your name in question please my name is humihiro naokawa from the University of Tokyo and I'm a master degree student of uh Universe cosmology and I want to ask about the diversity of hominin so you have discovered the mixture of homo sapiens and homonym deterrances and the fact is that only one space Homo sapiens remains now and do you think is the there's a is a 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 discrimination or War well it's striking I think that's a until 40 30 000 years ago there were almost always different forms of humans around on the planet the last 30 or 40 000 years is 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 then this even survived how would we deal with that today would we experience even worse racism against them than what we experienced 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 would 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's 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 okay thank you thank you to my left please your name and question my name is graduate student I want to be a researcher who can do pioning pioneering research like you do you have any advice or tips for keeping motivation for challenging big or long-term project you did yes I do get those questions now especially after this price and it's very difficult for me uh 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 you know that 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 very much you're writing embarrass me out okay very much I'm right here your name in question please I mean numbers hello my name is I'm in the Syria Senior High School so I risk them articles about you and he said like when you encourage the cow when you um get in getting into the college you plan to study about anthropology or science history but uh for you decided to like started to study about the medicine so this change sounds like really um shoes and my question is have you ever like met some like obstacles or difficulties to study like um like completely different subjects because for me at least on Dance topology and genetics seems like really isolated so my question is have you ever made some obstacles or if so um how did you overcome the problems yeah I think sort of my path was that I thought I wanted to do archeology and egyptology 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 it's important I think to have a university system where you can combine unexpected things that you combine things you're interested in and not have a rigid system that in many countries they now start where you set up you should study this set of subjects to become this profession because you become locked in into something rather than predetermined so I don't know how it worked 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 in question please hi professor pable my name is saki 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 neutrinos from collapsing 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 a quite a different field I'm faced with a similar challenge that you are 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 were you able to have such an unwavering focus on the seemingly impossible task of reducing the backgrounds and finding the tiny ancient Neanderthal DNA from the remains yes it's hard I mean I think you try to go around the problem right we realized that studying human remains was almost impossible because of the contamination you could not distinguish DNA from me yours whoever had handled the instruments from the endogenous being we turn to working on say mammoth because if you're from a mammoth get a DNA sequence that's elephant-like but not identical to an elephant you're very sure you have the right thing and then using mammals 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 and the end of the molecules that could show needed thousands of years to accumulate and appreciable amounts so then one could eventually come back to the humans and say we believe only this 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 in particle physics excellent thank you on my left your name in question please here today my name is enough so what did you usually play with Hillary 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 I think Winnie the Pooh and I don't know what I played I played very different things you know rather earlier 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 your name in question hello my name is green konishi and I have two questions and my first question is um when you started learning physiology and Medicine did you did it change your life 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 they 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 and that's where it still is I'm not back at the hospital yet thank you and my last question is is your childhood what was your dream well among the dreams was really being an archaeologist and finding exciting things thank you thank you okay up at the top your name and question please hello my name is Cesaro and thank you so much for today it was really inspiring and I'm still honored that I got an opportunity to ask you a question like this and I I'm a high school student and I'm really interested in Alpha apology especially cultural anthropology and I'm planning to go for alphability major from my college and if you have any advice for students who wants to um who wants to study anthropology or same kind of feel you're in I like to hear that it is so hard for me these questions about advice I really my only advice is really to follow your interest as I said to do what you think is important and interesting because then you can do 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 to my left your name in question please hello thank you very much for your lecture my name isaki um I'm a first year Bachelor of Science student at the University of Melbourne Australia and I aspire to be a listener in the field in a field of anatomy and Neuroscience but um people always tell me that being a scientist is not easy sorry not easy so um this is probably going to be a general question but my question is um what is the biggest hot soup you faced and how did you overcome it as a listener hmm 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 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's what you want to have out of your work life I guess thank you for naming your question I'm Enrico um I have two questions um how are you today I'm fine a little nervous and one question what what is like live in Okinawa it's very good I'm not there as much as I I would like to be but it's it's a great place especially if you like to do things in the water if you like snorkeling scuba diving it's a wonderful place thank you thank you thank you thank you okay up top your name and question please thank you for your good presentation and I'm a kosai Sasaki token University of Marine Science and Technology I have two question one is the annual 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 to know your method your or refreshment 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 intro to some insight that you hadn't expected what is really frustrating is when an experiment just totally failed for technical reasons that is is very frustrating but yes and second is what do you need a research environment what is oh just a sec okay please go ahead the research environment what kind of research environment is ideal do you have any requests about a 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 complement the expertise you have and that is also sort of open to collaboration where people work together under other 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 it's sort of 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 a thing forward so to an environment where you feel safe to even ask a stupid naive questions would be important such a things that I would sort of come up in my mind excellent thank you very much difficult question thank you very much yes I'm sorry but we do need to wrap up there for folks Still Standing please make your way back to your seats one last question Professor um could you tell us about an influential figure in your life and how they might have guided you well I think I was supposed to get 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 oyst 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 oyst and fans of science [Applause] if you if you would like to purchase Professor pabo's books his publisher has them for sale just outside now if you haven't been to ice you are officially invited to come visit us and say hello in beautiful onasan but until then thank you for attending this public lecture by sventepebo 2022 Nobel Prize winner and Adjunct professor at oist good night foreign

Channel: Okinawa Institute of Science and Technology (OIST)

Views: 4,693

Keywords: OIST, okinawa, science, technology, university, graduate, Svante, Paabo, genetics, neanderthal, evolution, human, denisovan

Id: mdYlD9--jy0

Length: 97min 47sec (5867 seconds)

Published: Mon Mar 13 2023