How to Clone a Mammoth: The Science of De-Extinction – with Beth Shapiro


So, as Emily said I’m a professor at University, California, Santa Cruz But I wear lots of hats in this life and one of them is that I am a national geographic emerging Explorer I’m not quite sure what I’m emerging from but so be it that’s what it’s called in any sense a few years ago in that capacity we were out in the field and Decided to put together a really short Overview video overview that was actually later used for a program called the world Science festival which is held in New York City Every spring and the program that I was involved in was called cool jobs And my role was to to prove that my job was in fact very cool It was in fact a competition between me and someone else and that person shot onto the stage with a robot Jetpack and then actually managed to raise himself in the air several feet so Yeah, I lost But in any sense, this is this is the video so and bear with the sound quality it’s slightly poor three four pieces of Mammoth here This is part of the vertebra you can see how big this is and the neat thing about this is that These are the small pieces which means that the stuff is washed Downstream? These pieces are actually still frozen in the permafrost. We can’t get them out at all which means our going to be really well preserved Just heard that big splash of water back there that means the other hole broken through Here comes the water we better get out of here So the last bits a little bit silly but in my defense that water is really gross, so That is in the gold mining district called the Klondike which is near Dawson City Canada’s Yukon Territory and what’s going on there? is that Gold miners collect water in big holding ponds every spring after the snow melts then they spray it up against this permafrost or the frozen Dirt that’s there and they washed away the layers that are fogged because of being hit by the sun They stop the warm summer sun melts the next few centimetres And they washed that away And their aim is to get rid of all of that frozen dirt and get to the gold-bearing gravels – that are beneath But in the process all of this dirt which is just full of decaying plant matter and animal matter and bones like those Mammoth bones that I was pulling out that have been there for as long as Seven hundred Thousand Years So you can imagine that it wouldn’t be very nice to all of a sudden be Splashed by water full of seven hundred thousand year old rotting plant matter right you want to stay out of that So I’m actually I’m a biologist or the molecular Paleontologist or a molecular biologist or a geneticist call it whatever you want But what is a biologist doing climbing around in the frozen stinky dirt collecting frozen bones? My research actually focuses on climate change and when we hear about climate change today? Or we see images of what climate change is causing often we see things like this Where changes in weather Patterns have resulted in massive desiccation in some parts of the world? Changes and storm patterns that can be incredibly destructive From flooding as well as droughts and of course different species that have been pushed to the brink of extinction And when we’ve read about climate change often what we see are crazy headlines. Just telling us that everything is terrible We’re all going to go to hell in a handbasket pretty much, right? But if you’re a biologist rather than just think about how awful It’s going to be one thing you might want to learn is how will the species and populations? Communities and ecosystems that are alive today respond to the climate change that’s predicted to happen over the next decades to centuries If you follow the climate change literature at all you’ve probably seen a plot like this one This is commonly called a hockey stick graph It looks a bit like a hockey stick on its side With a long end of the hockey stick and then the short end that used to hit the puck hockey over here, right? Sticking up on the other side that line across the middle is the average global temperature in about 1960 and what this is showing is a proxy for average global temperatures over the last thousand years So you see that’s thousand years ago to something around a hundred years ago the temperatures were about constant. Maybe declining Just a little bit and then when it then and then within the last hundred years the temperature has rocketed up about a degree Of course this plot can be extended forward in time, and there are predictions that show that it’s continuing to rock it up skyrocketing pace with massive global warming and lots of catastrophic consequences this of course is not the first time in history that the Earth has experienced a pretty massive global warming event if we Extend this plot backward in time the last 50 thousand years is now Shown on this plot through a thousand years ago this plot ends over here, or the top one begins. We see that around 20,000 years ago there began a previous rapid global warming event in fact between 20,000 years ago which was the peak cold part of the last glacial maximum the last ice age to around? 10,000 years ago the beginning of the Holocene Warm interval that were in today The global temperature average global temperature increased about eight degrees and this last period of increase that you see after a slight Stabilization there some work done in the klondike is beginning to suggest may have happened on the order of several decades to less than a century So that’s about a four degree Increase globally over a very short Period of time so what I do and people who are interested in studying the same type of thing? I am as we go back in time Throughout these last 50 thousand years and possibly even a little bit older than this and ask how did the species and populations? And communities that were alive that survived through this Transition from the Peak the last ice age into warm interval of today How did they respond to this period of rapid global warming the goal of this research is to try to figure out? How we can make better use of the limited resources and energy we have to combat the potentially devastating consequences of present and predicted climate change So the field I work in is called ancient Dna pretty self-explanatory means old DnA ancient not grandma But you know really going back in time the oldest Dna that we’ve been able to recover that We’re sure of the age is about seven hundred thousand years old and that was from a horse bone That was preserved where we shot that first video in the klondike near near Dawson City We know it was that old because it was found associated with a volcanic eruption an ash layer That was deposited when a volcano erupted that we can date to around seven hundred thousand years old It’s also the oldest ice the oldest permafrost. That’s known which is most likely why we were able to recover Dna from that bone the place that I work is called, Beringia, Beringia spans about from Alaska this part of the western Northwestern part of Canada across this bering sea and into One if you follow American politics at all, but remember from four years ago This was widely reported as the part of the world that Sarah palin can see from her backyard remember that Siberia of course yes So you see there’s some some white Colors there in the Ocean that’s just shallower bits of Ocean so during glacial Intervals when a lot of the world’s water was taken up into making Glaciers sitting on top of the continents the sea level was a lot lower and those white areas were exposed They were actually lands and this land bridge here that formed the entirety of Beringia was really important It was a conduit for exchange of plants and animals between Asia and North America things like horses and camels moved from North America Into Asia things like bison and people moved from AsIa into, North America So today this part of the world looks a lot like this I’m actually in that helicopter whose shadow you can see on the ground taking this photo below But during the last ice age it looked more like this with Mammoths Mastodons wooly in the Asian part of Beringia two different species of horse in North America there were giant camels there were bears that stood 16 feet tall and there was even the five foot tall beaver which is the funniest extinct animal So we fly out into this place and fantastic machinery like this you’ll notice that some of the windows are missing from this helicopter This is actually good because it makes smoking easier when you’ve taken off and are sitting on the gas tanks Not saying that happened Also, not saying it didn’t happen. We stay in the combination like this five stars as you see probably excellent ratings and Tripadvisor I took this by standing back from my tent and slightly unfocus in the lens, so you can see the depth of mosquitoes that You have to deal with when you’re up there, and we search for bones wherever the permafrost is melting This is back in Canada near Dawson City you can see that They’re washing down this parma frost with that water hose and there are folks from my group kind of wandering around looking aimlessly at the wall that were there, not washing down picking up the bones that wash out in in time and Tens of thousands of bones actually come out of this permafrost while they’re doing this we also Look for bones along Meandering Rivers where the spring snowmelt? Raced the Rivers rise and they cut around bends and pull bones off the the permafrost and deposit them around the next corner and in a day out Kind of collecting bones like this We can collect anywhere from five to twenty or even thirty bags like this of bones These are mostly bison bones. I have a geologist friends who calls bison the cockroaches of the pleistocene. They really are Incredibly Abundant in North America And nearly went extinct at the same time as mammoths and everything else went extinct in North America We also find Mammoths and Caribou and horses and if we’re lucky Carnivores populations of carnivores were smaller than those of herbivores, so their bones are more rare But we find grey wolves and and cave lions and these giant hyper Carnivorous Bears And from each of these bones, we’ll cut out a tiny little piece That’s just a standard dremel tool with a cutting disc take a tiny little piece back Take it back to the lab and extract DnA and using Statistical approaches we can correlate the amount of genetic diversity that we see in a population at any one point in time With how big that population is so lots of diversity means big populations not much diversity means small populations and we can also see things like Local populations going extinct and then being replaced by individuals moving in from a different place Lots of information in Dna that we can’t see just by looking at the fossils themselves And over the last couple of decades. We’ve learned a lot about how these Populations responded to these past periods of climate change we’ve seen bison horses and Mammoths Peak in Population size and then begin to decline something like an in North America something like 35 to 40 thousand years ago And this is interesting and important because the two main hypotheses about what caused the Megafauna mass extinctions within the last 10,000 years are that they really didn’t like the last ice age, but the peak of the last ice age was 20,000 years ago Or that people killed him, and there is no evidence of large numbers of Humans in North America until around 14,000 years ago so that these populations began to decline some 35 or 40 thousand years ago kind of lets us off the hook on at least the initial Stages of This mass extinction events not quite willing to let us off the hook for finally going driving them to extinction But we can talk about that later we’ve watched populations of Carnivores like Brown Bears grow and shrink and move across space really rapidly in response to Changes in the numbers of Herbivores that they’re using as prey and we’re starting to get a better idea of why some species like Reindeer Caribou same thing are alive today they don’t like to live where humans do which is a pretty good trick and things like cave lions are extinct and Whenever we finish some of these analyses And we write up our papers and we get them published they often go in pretty nice High-Profile journals and people like to hear about it mammoths are cool Right and we get calls from the popular press and from my mom and everybody’s really excited about what’s going on And I’m super excited to tell them about what we’ve learned and how we can apply this to questions That are it’s about the biodiversity that’s disappearing today, but they only ever ask me one question And to be honest is kind of annoying And that’s why I wrote this book there really is no sound bite-sized answer to this question and so here we go so now we have this field called D extinction De-extinction, it’s a terrible word right and the reason that I hate this word the most is because it is impossible to conjugate without Sounding like an idiot right, how do you say that you have brought something back to life using this word. Do you say you have? De-extunct … De-extincted … it’s terrible right awful? Of course, we’re all very familiar with De-extinction because we were around the last time it happened and Everything went swimmingly obviously no problems whatsoever here is the premise behind Jurassic park was that Dna was extracted from Mosquitoes that happened to be preserved in Amber and the scientists were able to take that DNA and piece it together Fill in the missing pieces with frog Dna which I still don’t understand given that even at that time we knew that birds and reptiles were more closely related to dinosaurs than frogs but License to do what you want, I guess it’s the movies Turns out that Dna is not well preserved well preserved at all in Amber in fact About ten years ago there was a team of scientists that tried to see whether or not they could recover Dna not only from Amber but from a much younger precursor to Amber copal they took pieces of copal that were only from the 1950s and 1960s from the collection that’s natural history museum here in London and also pieces of Amber and they selected pieces that had Insects in it and pieces that didn’t have insects in it And then they extracted DnA and tried to amplify Insect Dna thinking if there is stuff it preserved in there if there is DnA in there It’s gonna be insect DnA and they did manage to get insect DnA out of these pieces of Amber unfortunately there was no correlation between getting insect DnA out of Amber and Kobol and Actually having insects in that amber or copal Which is just one of the problems that we’ve come to deal with an ancient Dna that DNa is Everywhere and Dna from insects in particular is very prevalent Turns out Amber forms in a very hot place and hot is bad for DNa survival It’s also very porous and Microbes Bacteria can get into that Amber and these living organisms Just catabolized chopped up eat that Dna destroying it very quickly So there is no Dna in amber of course there are dinosaur bones so why not just collect dinosaur bones take a piece out of them with a Dremel tool like we do with Mammoth bones grind it up and extract DnA Well dinosaur bones are rocks and rocks don’t have Dna right so we can’t clone dinosaurs Of course we do have tons of incredibly well-preserved Mammoth bones that we’ve been picking up across the Arctic and we know that there are Mammoth mummies that are incredibly well-preserved that contain intact organs And what looks like muscle structure and skin and bones these things are incredibly beautiful and really well preserved And that’s why we are going to use Mammoths as the source of how we walk through how we might bring something back to life so not how to clone a dinosaur But how should we clone a Mammoth? And in the next 30 minutes or so I will walk you through the process of bringing a mammoth and potentially some other species back to life there are three plans three different plans that I’m gonna tell you about and they kind of increase in order from Really really wonderful to quite spectacularly wonderful so bear with me as we go through these first let’s clone a Mammoth This is what the book is called. This is what people generally think about Cloning is actually a very specific a specific scientific technique that’s actually known in science words as Somatic cell Nuclear Transfer So we have two types of cells in the body germ cells those are sperm and eggs and somatic cells which are everything else Normally sperm would come together Fertilize form a zygote zygote has a special type of cells stem cells that are able to become Every type of cell in the body somatic cells are already very specialized they have a Specific set of instructions to be a type of cell a hair cell a cheek cell a muscle cell Mammary cell a heart cell but they can’t become any other type of cell They’re fixed in becoming the type of cell that they are instructed to be so the trick to somatic cell Nuclear transfer is to take one of these specialized cells and convince it that it’s the same type of cell that you would find in a zygote in a developing Embryo that it has the capacity to Revert to this primordial form and become Every type of cell in an entire organism So as Emily brought up the most famous example of somatic cell nuclear transfer Is the cloning of Dolly the Sheep which took place in the mid 1990s the Roslin institute in Scotland? So when dolly was cloned they took some somatic cells mammary tissue cells from a particular white? Ewe … this guy up here in the corner and they put them in a dish in the lab and Starving them of nutrients stressing them out at the same time they took egg cells unfertilized egg cells from a different breed of sheep So that they looked different from each other and they removed the nuclear material suck out the genetic material from this unfertilized egg so that it was an empty egg with no Dna in it they stick these two close together and zap them with a Bit of electricity causes the Membrane in that cell to break open and the genetic material from that somatic cell to dump into the inside of the egg Then you zap it again and the proteins in that egg cell Can magically cause that somatic cell to forget all of the instructions necessary to be a mammary cell and revert To that early type of cell that is then able to become every type of cell in an entire sheep you then? Develop it for a little bit take the developing Embryo Implant it into a surrogate host in this case was yet another breed of Ewe so you can see all the differences between the individuals There and the the sheep that was eventually born dolly was a genetic clone of the somatic cell the Mammary cell donor not of the egg cell donor or of the surrogate host So how would this work with a mammoth we go out into the field we find that incredibly well-preserved Mammoths we take his cell and we stress it out in the lab starve it of Nutrients, so that it’s kind of confused and doesn’t know what it’s doing We stick it inside an egg cell probably an elephant egg Cell that zaps it and causes it to revert to that early cell We stick it in an elephant that grows up into a baby mammoth and then we release it into the wild So we do find an Incredible diversity of remarkably well-preserved Remains in the Arctic this horse jaw that’s up There is probably somewhere around fifty to a hundred thousand years old and yet It looks like it could be a couple years old found outside We do find incredibly well-preserved Mammoths and a Few years ago There was this expedition up to the new siberian islands that found a mammoth you may have heard it in the news that was supposedly Associated with this thick red Viscous substance that they thought might be blood it turns out that it probably wasn’t blood, but it was nonetheless remarkably well preserved and Yet none of these remains and none of the remains that will ever be found from a Mammoth Contain a living cell When an organism dies the DnA and the cells that contain that Dna begin to decay? Almost immediately first by enzymes that are in the body itself And then by things like oxygen and water freeze thaw Uv Radiation from the sun hitting those bones when we walk outside Uv hits our dNA and causes mutations But we have proofreading mechanisms that can go and make fix that mutations so that we don’t get cancer every time we walk outside Once an organism is dead those proofreading Processes can’t work anymore because they require energy of course when an organism is dead. There’s no more energy. The soil itself is full of microorganisms that Infiltrate the bone in the tissue and start breaking down that Dna mummies it turns out tend to be even more poorly preserved Than bones that are completely defleshed and buried and quickly frozen one hypothesis to explain this is that the gut contents which of course? Contain tons of Bacteria Burst and those Bacteria go throughout that Mummified body breaking down the DnA So we will never find in any Mammoth anywhere. That’s found no matter How well-preserved it appears when we first look at it a living cell and where there is no living cell We will not be able to clone a Mammoth Thank you for coming Just kidding. I already told you there were three right okay, so Now emily pointed out or noted early on that a few weeks ago this international team of scientists Led by the group from Stockholm sequence and assembled the complete genome sequence Of actually two different mammoths there was one from wrangel island that was around 3,500 years old and another from Siberia that was around 4,000 years old so with these two Complete genome sequences and there are actually a couple more complete genome sequences of mammoths that have been sequenced and published now We now have this blueprint this very long list of A’s, C’s, G’s, T’s … the letters that make up your dna that contain the genes that make the proteins that make Mammoths look and act like Mammoths So surely we could just go into the lab and then Artificially synthesize these long strands of a’s c’s g’s and t’s stick these into chromosomes Which of course is how its assembled in the cells and then get those chromosomes into the cell and then we could do that thing? Where we put the cell and it does the when you come around than that? Yeah? Well to explain why plan b. Is potentially not what’s going to work. Let’s begin by Focusing on what we mean by complete in the complete genome So as of today, there are no Vertebrate species for whom a genome has been completely sequenced and assembled and that includes us even though there are Very many human genome sequences out there the problem Is that there are parts of the genome that are very hard to sequence through now admittedly? We do have most of the human genome that we think is important most of the parts that have the genes that make the proteins But there are parts of every one of our chromosomes that are made up of these tightly condensed repeat regions Sometimes near the Center the chromosomes other times near the end also scattered throughout the chromosomes But there is no existing sequencing technology that we can get through We don’t know how important these regions are we think they don’t contain genes but they do have some role to play and we don’t know how long they are and we can’t sequence through them so we can’t actually start from one end of a chromosome and Go into a lab and just build that chromosome using a’s c’s g’s and t’s we don’t know how to do that The situation is even worse for something that is extinct and there are two main reasons for that The first is that the sequences that we recover from a Mammoth bone or a Mammoth Mummy are? Very short, and they contain all sorts of chemical damages that make them hard to read this is because of the the stuff that I was talking about just a minute ago where the Uv light is hitting them and Freeze-thaw is breaking things down and Bacteria are chewing the sequences up So if you imagine that a modern Dna sequence is like a very long lovely party streamer that you can sequence Millions and millions of bases at a time the stuff we get out of mammoths is more like Confetti but not confetti like this in fact I couldn’t find a picture of Confetti from the day after the parade that had been brushed into the gutter with the other trash that had been left behind and had Rained and There were elephants in the parade and a flock of passenger pigeons flying it anyway. It’s really terrible It’s really disgusting the second reason is that When you extract dna from a piece of Mammoth bone or a piece of tissue you don’t just get Mammoth DnA so if I were to take a piece of my own hair or swab from the inside of my cheek and Extract Dna and then sequence everything that’s in that extract a process called shotgun sequencing We just want to know everything that’s in there The result would look something like this where most of what I recovered was my Dna. That’s because I’m alive I’m not particularly damaged or contaminated as far as I know right about 10 years ago I was involved with the first project to do this type of sequencing shotgun sequencing on a mammoth We took a mammoth bone from Siberia that was around 25 or 30 thousand years old and we extracted DnA and then sequenced Everything that was there and then you take each of those little tiny broken fragments And you figure out what each one is by comparing it to this enormous database of everything that’s ever been sequenced Right and there’s some elephant genome. That’s available So presumably the bits that are mammoths are going to look like they’re closely related to an elephant and what we get is this We’re about half half of the data that we recovered Actually matched the elephant and so therefore was likely to be mammoth the rest of it was other stuff Mostly soil Bacteria you see that big chunk of blue. That’s unidentified. That’s probably also soil Bacteria there’s a huge diversity of Microbes that live in the soil that we have not sequenced yet, so they’re not on that public database So of course it would just come back as who knows what it is and but it’s not Mammoth right so about half and We were pretty depressed about this right if every time we do this sequencing We have to throw away half of the data. We generate because it’s not actually what we’re looking for then It’s gonna be way too expensive and time-consuming to ever sequence a complete ish, Mammoth genome It turns out. This was an incredibly well-preserved Specimen and in the last ten years we’ve seen that most of the remains that we work with and things are a little bit better in the Permafrost than they are if you’re looking at cave specimens or more recent specimens most of the time we see something between about five percent and twenty percent of what we get is actually what we want and the Rest of it. We throw away a Few Years ago the team from leipzig from the Max Planck institute and leipzig sequence and assembled the first Neanderthal genome and they used a couple of different bones in this approach for each of those bones less than 1% of the Dna that they recovered was neanderthal they had to throw away more than 99% of the data that they were generating So instead of looking for just the confetti that we’re finding in the gutter after the parade We’re actually looking for just the purple pieces of the Confetti which is really hard to do And this is a major problem of course We do live in an era where there a lot of genomes that have been sequenced and assembled This is how we make sense of the stuff that we can get out of these bones? so if we are trying to sequence and assemble the Mammoth genome We have the elephant genome as a scaffold a kind of map that we can line up on our computers And then take each of those little pieces and see where it fits in across that elephant genome and if we’re interested in seeking then Sequencing the Neanderthal genome we have a lot of human genomes that we can line up those pieces and see where they fit This is great, but it’s also kind of a problem in that if you imagine that there’s some big evolutionary difference between a Mammoth and an Asian elephant say a Mammoth had some big Duplication event and there’s a whole bunch of Dna that Mammoths have but elephants don’t We wouldn’t have that in our scaffold in our map and because there’s so much stuff that we don’t know what it is we would probably just throw all that stuff out thinking that it was just another batch of soil Microbial DnA and If we’re really interested in knowing what the most important difference is Distinguishing Asian elephants and mammoths are then one might think that those parts are actually kind of important, but we won’t see them Another problem is that even if we could generate this long sequence? it’s not the same thing as having a Living cell which remember is what we need if we’re going to then go ahead and clone this thing So we are getting better at stringing together long? Sequences of a c’s gs and t’s but we can’t go that long before the technology we have starts making mistakes We don’t know how then to take these long sequences and wrap them up in such a way that Sticks them into chromosomes and allows them to turn genes on and off and even if we could do that We can’t actually insert chromosomes into cells, so if plan B Is the way that we’re thinking we’re gonna go we’re pretty much stopped at Step one This kid gets a lot playing my talks. He’s a very sad kid Of course there is another way and plan C This is the plan that is most likely to be the one that one might use to bring an extinct species back to life And so this is where I’ll be spending the rest of the time trying to try to spread it out. What before we? – before I get into the details of this I think what’s most critical to understand about Mammoths and Asian elephants is that they shared a common ancestor relatively recently in evolutionary time about 6 million years ago or so and as such they share about 99 percent of their genomes, they’re 99% identical so when we have an Asian elephant We already have a 99% Mammoth right so all we have to do if we’re Gonna engineer a mammoth or take that Asian elephant And slowly change it so that it’s more and more mammoths like is to identify that last 1% and swap that out And that’s what this is kind of in a very Over overly simplified way of thinking about it. It’s kind of like a cut and paste job Where you line up your dNA? Sequences you find where mammoths and elephants are different you cut out the elephant version and paste the mammoth version in its place So we now have several different Asian elephant genome sequences And we have several different Mammoth genome sequences and we can start to compile a long list of places where Asian elephants look like one thing and Mammoths look like something else and We think that these are potentially important differences between them and these are the places that we’re going to cut and paste So imagine that we had a machine that we could program to go to a very specific Place in the elephant genome we could send this machine into an elephant cell in a dish in the lab and it would find exactly the same place every time because you’ve given it very precise instructions about where to go and You could give that machine a little packet to take with it in this case the package would be as small artificially synthesized strand of Mammoth Dna and this machine you could inject into the cell with this little package it would find Exactly the place in the genome that you wanted to change it would grab ahold and chop it out chop out that Elephant version of the Gene so that the mammoth version could be stuck in there in its place Well we have that machine and it’s not something that is artificial something that we’ve made up It’s a naturally occurring protein enzyme complex. It’s found in Bacteria and Archaea and is used by them to fight invading Pathogens to to stop themselves from getting killed by disease It’s called crispr crispr Caste 9 you’ve probably heard about it in the news recently because it’s incredibly powerful and super scary But we’re not going to go there just now right This crispr caste 9 system is our little machine and here. We have this red strand That’s the elephant Dna and the blue strand is the way that we tell this machine exactly where to go in the genome to find That precise bit of elephant Dna that we want to change and we send the crispr caste 9 system into a cell along with this synthesized piece of elephant Dna it Finds the place in the genome it wants to go and it cuts the dna strand cuts both strands of that double-sided DnA Now cells don’t like it when the DnA is broken. It’s not good for cells It makes them die and so evolution has created a couple different mechanisms to fix these types of breaks so the next step in this process is to harness the cells own repair mechanisms to make to close that Gap and In closing that gap to actually stick in that synthesized piece of Mammoth DnA So you end up with an elephant that is a little bit mammoth like Just a little bit So what what we want to change? We can use this technology it does exist. So what should we target? well, there is starting to be a long list of genes that are potentially different and important between Asian elephants and Mammoths the first of These genes to be identified was identified about five years ago by Kevin Campbell’s lab in Manitoba. I went backward Sorry, and they found that the hemoglobin which is a protein in red blood cells which are responsible for carrying oxygen Around the body they found that the woolly Mammoth Version of part of this hemoglobin complex was different from the elephant version the Asian elephant version by only three changes these three lines that you see on the tree here relating to woolly Mammoth and They made both of these Molecules in addition the lab and wanted to know why so what what are the consequences of having these three difference? and they measured how well these red blood cells carry oxygen around the body at different types of phs and different temperatures And they found that these three changes just these three changes Were sufficient to let that woolly mammoth version of the red blood cell carry Oxygen at much higher efficiency when it was cold so this is very clearly an Adaptation that evolved along the lineage to wooly Mammoths as they moved out of their tropical Habitats the common ancestor moved out of the tropical habitat into somewhere cold So what else? So from these data that we have these long lists there are well There’s one team of researchers based at Harvard the wyss institute there and Led by George church Who’s the guy over here on this side that have been? Compiling a list of these genes and designing these crispr casts arrays to actually swap out Mammoth genes in to swap Mammoth genes into Asian elephant cells growing in a dish in a lab And they have so far attempted to make crispr cast molecules to change 14 genes 14 different genes and they have succeeded at Changing 14 genes all of them every single one of these has worked so far So they now have in a dish in their lab a cell that is a very small amount Mammoth Of course that’s very different from having an actual living breathing Mammoth But it does tell us that at least this first part of plan C. Is something that is potentially doable We do have Mammoth genome sequences We do have this genome editing technology in the crispr caste 9 system And what that gives us is a cell a living cell an elephant cell with a little bit of Mammoth DnA Injected into it that we could then clone using somatic cell nuclear transfer then the next step of course would be to put it into a surrogate host have a grow up and move out somewhere and Be happy right I like to call this second part of the extinction phase two phase two has not received as much attention by the Popular media or as phase one has you kind of hear in the news about this genome sequencing and about these People have swapped out these genes and the conclusion is that tomorrow we’re gonna have Mammoths tomorrow Mammoths will be wandering through the countryside, and isn’t it going to be wonderful? Well, that’s not true because we can’t do this right We can’t do that part it turns out that there are Technical hurdles in the way here that there are intricacies of the elephant reproductive system which means we can’t clone Elephants one important component is that elephants have a hymen that grows back between each pregnancy you can imagine that a baby? Developing an embryonic elephant is actually quite a heavy thing right and this hymen has a hole in it That’s small enough for a sperm to pass through But certainly not something that a developing elephant Embryo could pass through so until we can solve that particular Technical Hurdle cloning is just not something we can do with elephants Not to mention problems with growing up something that’s a different species inside a surrogate host or finding a place for it to go so stepping back a bit from talking about elephants now to think a little bit about the feasibility of Phase 2 of de-extinction of course mammoths are are not the only species that is are being discussed as a potential candidate for D extinction there are lots of different species I’m kind of convinced that people only talk about Mammoths most frequently because it’s it’s getting to be common knowledge that we can’t clone dinosaurs and mammoths are the next best thing But there are other species that have been suggested, so the first step in phase two would be to find a surrogate host so with some species it should be relatively straightforward to find a surrogate host species that have very close living relatives for example like the Bucardo this ibex that went extinct that used to live in the pyrenees that mountain goat that went extinct in the early 2000s there are other subspecies of mountain goat that would make reasonable surrogate hosts for a developing Bucardo, but the more evolutionary distance there is between the thing that is extinct and the thing that you’re trying to use as a surrogate Host the Harder it might be for that surrogate host to actually bring that developing Embryo to term in some cases there may even be Physical constraints associated with Carrying a different species inside your body probably not true with Mammoths and elephants I was really excited to write this part of the book where I was gonna talk about how horrible it would be for an asian Elephant to Carry a Mammoth, so I wrote an email to adrienne lister. Who’s at the natural history museum here Who’s probably the world’s Mammoth expert and I said oh tell me tell me how big Mammoths were he was like Oh, they’re about the same size as Asian elephants But in fact there are some species that are candidates for the extinction where there would be physical constraints my favorite example is Steller’s sea cow that’s this guy here at the bottom yeah And that’s a scale right there scale so these stellar C-cal they went extinct a couple hundred years ago They lived off the coast of California across the aleutians and into the commander islands Apparently one of these could feed a crew of 30 to 50 men for many weeks, which is probably why we killed them all? so the most the the closest living relative of Steller’s sea cow are dugongs and Manatees and if the same size ratio applies to Newborn dugongs and Manatees and adult female dugongs amenities as Applied to celler sea cows, then a newborn Steller’s sea cow would be decidedly larger than its mom Probably not going to work It’s also true that’s we and every other organism are much more than the sequence of our genomes in fact we are a combination a product of the sequence of our genomes and the environment in which we live Anyone who knows identical twins that are elderly knows that by the time these individuals are? Even you know 50 60 70 years old, not that 50 is elderly. Sorry my mom would kill me if I said that Call myself elderly before long here um anyway But the time these individuals are in their 70s and 80s these individuals are Sometimes you can’t even tell they’re related to each other they look different, physically look different their genomes are identical Right the differences in their appearance are due to the different experiences that they have during their lives There are different stresses there different diets the different things they were exposed to and that exposure starts prenatally So we’re already talking about a species if we return to elephants and Mammoths that are 99% identical at a genetic level if we swap out a few genes And we have this developing embryo growing inside the body of an elephant that developing Embryo will be exposed to elephant Hormones and an elephant diet and elephant stresses it will be born to an elephants and elephants when they’re born they will eat the poo of their moms to Establish the community of Bacteria that they require to break down their food We’re beginning to know We always hear every week you have hear stories in the news about how important the Microbes that live in our guts are to making Us look and Act the way we do this individual will have an elephant’s gut microbe it will be raised in a community of elephants and consume an elephant diet or whatever it is that elephants are fed in Captive Breeding environments and speaking of captive breeding environments There are of course Ethical considerations, and this is the point at which mammoth de-extinction to me becomes something that we should not do We know very well that elephants don’t fare well in captivity elephants often fail to reproduce in Captivity if they do they sometimes injure even kill their young until we’ve learned how to meet the physical and psychological needs of elephants in Captivity We shouldn’t be keeping them in Captivity at all much Less using them in these kind of crazy harebrained scenarios where we might be bringing something extinct back to life Of course every different species that we consider for the extinction will have different technical and ethical considerations along with it and there may be species where the ethical considerations are not as dire or important as it is with Mammoths and finally it would be remiss of me not to acknowledge and point out that the environment in which these species lived has changed considerably since they went extinct and Environments, and ecosystems are of course not static It’s not as if an ecosystem and an individual goes extinct in gaping hole remains in an eCosystem You could just slot this individual back into it will change it will adapt new Species will come in This picture here is this is the lake this is through the great lakes in the Eastern Coast of North America taken from night This is the native range of the passenger pigeon Which is one of the species that has been considered for de-extinction? passenger pigeons went extinct about a hundred years ago when Europeans first arrived in North America they noted that these birds flocked in the billions in fact the first official census of passenger pigeons by European who arrived and saw them flying in newfoundland was that there were an infinite number of them? Where would we put in the infinite number of passenger pigeons in this ecosystem? Where would we put them where people wouldn’t just decide that they wanted to make them re-extinct, right? So de-extinction can we do it? Not yet but the technology does continue to Advance and All Sorts of technologies are evolving there may even be some day where we could bring a mammoth back to life without? evolving involving elephants at all So I have to say that we can’t yet put this qualifier on it because I do believe that at some point We will be able to bring extinct species back to life But I think a bigger and possibly more important question is whether we should? and As someone who has written a book about this clearly I have a official and very very sincere and absolute position on this and I do I Don’t know I Think it really depends on which species that we’re thinking about bringing back and our motivations for doing so so there are several different d extinction processes that the extinction Projects that get a lot of press. There’s a heath hen project This is the Prairie chicken that used to live on Martha’s vineyard the passenger pigeon here these are projects by revive and restore out of San Francisco The Gastric brooding frog which swallowed its tadpoles and barf them up as fully-formed frogs I would like to see that thing back just cuz that’s pretty freakin cool Tyla seen the Wooly Mammoths here’s the arak. There’s a back breeding project in the netherlands to Resurrect the thing that was ancestral to all of our living domestic cows This is the Bucardo from the pyrenees picture of one of the last individuals that was alive And this is of course the Stellar Sea Cow In each of these cases we hear a lot of news about progress. That’s being made But there actually isn’t that much progress being made because these teams are really focused on just trying to understand the technology as best They can on the budgets that they have which is zero, right? All of this work is being done in the back corner of somebody’s lab You know just waiting for some technical breakthrough from a different field to allow them to move forward But these people aren’t just doing this haphazardly I mean I all of these groups when we have these discussions and meetings are very deeply concerned with trying to as We see whether it’s technically feasible Really decide. Why why do we want to bring these things back to life? And just to illustrate the thought process that goes to this I’d like to step back to talking about the Mammoths and ignoring that it’s technically not possible to bring a mammoth back to life and ethically a Terrible idea to bring a mammoth back to life in something that we shouldn’t do What are the reasons that we might want to consider doing this should the technology advanced to the point where we can? And I can think of two reasons … two reasons that we might want to have mammoths the first is ecological There’s a place in Northeastern Siberia up here near Cherski in Russia Sergey Ziemov – the head of the North East science station the Russian academy of science has been buying up land since the Mid 1990s and he calls this land Pleistocene park the Pleistocene was the time period When we had these big beasts before the holocene, which is the interval we’re in today Obviously he’s thinking about the movie right, but Pleistocene park And he’s preparing his pleistocene park for the return of the ice age Beasts and so far he has bison from Canada Horses about five different species of deer and he’s been doing some experiments with these guys where he’s allowing them to graze in some parts of the park but not in other parts of the park to See what the consequences of having these animals on the landscape are and here’s a picture that Sergei took One early spring and so there aren’t animals on this side to the side with the house, not grazing and you see that There’s about one one grass species there. It’s not a particularly productive part of grassland certainly not sufficiently productive to Sustain a large population of grazing herbivores on the other side of the fence He does have herbivores and you can’t see it very well, but there are green patches here And those green patches are pretty diverse there are a lot of different species of grass and tiny shrub that have come up started to Started to grow in these areas where he has these grazing herbivores importantly. This is really early spring So nothing has had time to regenerate just yet so all of that green stuff That’s there is actually still there despite having grazing herbivores and lots of them on this land throughout the very harsh cold Months of a siberian winter just having these animals on the landscape has been sufficient turning the soil recycling nutrients moving seeds around they have essentially created the habitat that they need to survive and Not only has sergei seen the growth of these populations naturally in Pleistocene park But he’s also seen things like Saiga antelope that live elsewhere in Siberia But often struggle to find enough to eat come and visit the park because it’s just such a rich resource He points out That’s the largest herbivore the mammoth may like the elephant does in its environment play a particularly important role That is still missing any tries to make up for it sometimes by driving around with Massive like road making machinery Butts you know but it’s clear that these herbivores have already Reestablished these interactions that have been missing since these animals went extinct for so long And this to me is one of the most compelling reasons that we might think about bringing species back If there are interactions that are missing because of an extinction that could be reestablished to revitalize that habitat not only Because we want to bring something back, but to save the species that are there today That in my mind is a compelling reason The second reason is more emotional Few of Us can imagine a world without elephants and yet Asian elephants are Endangered and every year there are fewer of them and their habitat is declining as human populations grow and we’re struggling to keep Poachers away from them to kill more of them What if we could use this technology not to bring Mammoths back to life? But to edit the genomes of Asian elephants in such a way that they were able to survive in Colder habitats we could Expand the range of habitats that these animals could live they could live in Europe or North America or even Pleistocene Park in Siberia What if we could use this technology not to bring something back that’s been gone for a very long time But to save species that are alive, but endangered today Why not continue to think big about what this type of technology might do? Black footed ferrets are a population of little grubby things actually not grubs They’re very cute that live across the central plains of North America over the last couple decades. There was a massive Extermination program to try to get rid of them and people thought that it was successful until a small Population an isolated population of surviving Black footed Ferrets was discovered Unfortunately there were very few founders in this population and their genomes are Nearly identical and today. There’s a disease that’s killing them that they do not have any immunity against There are black footed ferrets in these in collections that date to the last twenty thirty Thousand years And there are black footed ferrets in a really cool collection called the frozen zoo that’s in San Diego Associated with the San Diego zoo where oliver ryder has been capturing tissue samples of things that are alive But endangered for the last couple of decades and he has black footed ferrets that are not from this population from a different population with much more genetic diversity What if we could use this technology to isolate the parts of the genome that provide? immunity Diversity and Immune response from these frozen and Museum Black footed Ferrets and Insert swap out the part of the genome in the genetically identical black footed ferrets with this increased diversity Could we use this technology? Potentially to increase the response of this population to the disease that’s killing them in fact saving this population from extinction de-extinction isn’t possible and it’s crazy right and There is absolutely no way that. We’re ever going to recreate something that is a hundred percent identical to a species that is long gone But the technology behind de-extinction. I feel has a tremendous potential to reframe our Possibilities of what we can do to try to fight the sixth extinction the extinction crisis that’s going on today to save species and habitats and ecosystems that are alive today and That I think is the most important and potential use of this technology Thank you you

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