Particles of Thought

BETH (00:00):

How do you get informed consent from a Neanderthal to be brought back to life?

HAKEEM (00:05):

Simple. You bring them back to life and ask them.

BETH (00:07):

And if they say no?

HAKEEM (00:09):

That question answers itself.

(00:24):

Hello, everyone. Ever wonder if we could bring back a wooly mammoth? Well, our next guest, Beth Shapiro, is hoping to make that sci-fi dream a reality. She's an evolutionary biologist and chief scientist at Colossal, the folks who recently made headlines for the de-extinction of the dire wolf. No biggie, just bringing ancient predators back to life. Now, let's get into it.

(00:50):

Dr. Shapiro, welcome to Particles of Thought.

BETH (00:53):

I'm excited to be here.

HAKEEM (00:55):

Thank you so much for coming. I know you're really busy bringing all these species back to life so thank you for ...

BETH (01:03):

I had to step out of the lab for a minute, it's a tough job.

HAKEEM (01:07):

Yeah, all right. So, let's talk about your baby wolves. So, how old are they now, the three?

BETH (01:12):

Well, Romulus and Remus will be one pretty soon, they were born in October. And Khaleesi was born in the end of January.

HAKEEM (01:22):

And what-

BETH (01:22):

So, yeah, so they're approaching their first birthdays.

HAKEEM (01:25):

What are their personalities like? I have a dog that just turned one and this animal has chewed up everything in the house, okay, and it can jump unlike any dog I've ever seen. So, is there anything in their personality that you can say, "Oh, this seems more dire wolf than it does gray wolf?"

BETH (01:45):

Well, they're still young and all three of these animals have lived with people for much of their lives. The last time that I was able to see them was a couple of months ago and it was the first time that I'd been in a closure with Romulus and Remus and felt a little nervous. So, they are definitely way more wolf-like in their behavior than they were even five, six months ago, they really don't want to get close to you. But they are different from each other. It used to be, in the very beginning, Romulus was more likely to come up to you and hang out and see you and he has become really like, "I don't trust you. I don't like you," and he's really big. They're about 115 pounds now and so it's a little bit-

HAKEEM (02:29):

Oh, wow.

BETH (02:29):

I'm 115 pounds so this is not something that I'm very excited about hanging out with. And so, you walk in there and you think, "Oh, they are dire wolves, I am probably not supposed to be here." But when I was there a few months ago, Khaleesi still had been in that puppy phase and she wasn't yet in the large expansive enclosure with her brothers, she was still kept a little bit separate from them. We've since started to introduce them and that's going really well but I walked right in and the first thing she does is jump up on you and put her giant, giant wolf paws on your shoulder and she started chewing on my collar and I'm thinking, "Oh."

HAKEEM (03:05):

Oh, boy. Oh, man. Those are fangs right next to your neck. You're a brave researcher.

BETH (03:15):

Yeah. So, she, at some point, will have more of these behaviors but she's still a puppy, she's lovely though. And it's so inspiring to see this. You spend so much of your time in the lab staring at a dish, staring at things you can't see to actually be able to see these wolves, to see the dire wolves running around in this secure and expansive ecological preserve has just been ...

HAKEEM (03:44):

That is amazing.

BETH (03:45):

I don't know, it makes me emotional just thinking about it. And, also, to know that ... The thing is, the traits that we modified, the size and the musculature, they're obviously not things that are immediately obvious when they're born. They were large puppies but, at the same time, that could be because there weren't that many of them in the litter and so they're larger because of that and now they're definitely large and we can see the impact of the edits. But when they were born, they were white, they were white and most wolves, when they're born, are dark-colored and so you could look at them and you could go, "It worked. We did it." We modified the sequence of their DNA and that phenotype is what we see. We have made these dire wolves using ancient DNA and very precise genome modification and this is an incredible step forward for synthetic biology for conservation, synthetic biology for de-extinction and using a combination of de-extinction and synthetic biology genetic rescue for real re-wilding, for real ecosystem scale conservation.

HAKEEM (04:53):

Oh, interesting. Okay. So, let's do two things now. Let's define some things for our audience. So, the two things that I want to define or describe from you. One is what does it really mean to de-extinct and the second thing I want you to get into is how do you do it. What's happening in the lab?

BETH (05:15):

How long is this podcast?

HAKEEM (05:16):

As long as you want it because I'm interested. How often do I get this opportunity? I got Dr. Beth Shapiro, I'm asking ... I want to know.

BETH (05:28):

So, our goal with de-extinction is to be able to create versions of these extinct species that are able to thrive in habitats of today that resurrect using DNA, using ancient DNA, extinct traits. And by creating these extinct species, by bringing extinct species back to life, our goal is to restore missing ecological interactions so that we can make ecosystems more robust and more resilient. So, Romulus, Remus and Khaleesi, we intended to bring back traits including the size and the musculature and we really liked the light-colored coat. We didn't know that dire wolves were light-colored until we sequenced the ancient DNA and were able to see in the sequence of their DNA that the animals whose genomes we'd sequenced both had light-colored coats. And this is actually a really important way of really showcasing how we are concentrating on de-extinction but also on animal welfare.

(06:29):

So, we knew that we wanted to make these light-colored animals. The gene variants that were in our ancient dire wolf fossils were in a gene that, in modern gray wolves, if individuals have variants in those genes, they can sometimes be blind or deaf. It's not the same variant that we saw in the dire wolf fossils but it's in the same gene and we thought that's a little bit risky. But since our goal is to bring back phenotypes, we know that we can make a gray wolf background into a white animal because there are white gray wolves today. So, we will use those variants to bring back, to de-extinct this dire wolf light-colored coat and, in this way, we are ensuring that we are bringing back, we are de-extincting dire wolf traits in the safest, most ethical way possible. So, how do we do it? Okay.

HAKEEM (07:21):

Wait, wait, let me ask a question about that. So, I've heard this with respect to the human genome but you can map specific physical characteristics to specific genes and you can say, "Okay, this particular gene," for example, light skin occurring in humans and anatolia or something like that, we know what gene created that. So, is it the case that you take a existing genome of, say, a gray wolf ... Oh, you know what? I'm getting to the question I'm about to ask you and then you say, "Okay, let me add the particular genes that give me the dire wolf characteristics to that existing one." Or, do you say, "Hey, I have this incomplete dire wolf DNA profile and let me fill in the gaps with living gray wolf." Which ...

BETH (08:13):

You know what? That is the Jurassic Park versus the way we're actually doing it conversation which you had said. So, I think that's why people are confused because Jurassic Park, which can I just remind everyone who's watching right now that Jurassic Park was not a documentary, that this was a science fiction. I think sometimes people get a little confused and they think this is what we're doing. And I'm also going to admit that I am an ancient DNA scientist who has attempted to extract DNA from insects preserved in amber and the hardest ... Of course, I did. And the hardest part about that was actually smashing the amber because it's so sticky. I had to freeze it really hard and then take a sledgehammer and whack the crap out of it so it would shatter and then try to find the pieces with the ... Anyway, there is no authentic insect ancient DNA or authentic dinosaur ancient DNA in amber.

HAKEEM (09:09):

Got it.

BETH (09:10):

Amber's actually a really bad material for the long-term preservation of DNA because it forms in really hot places and that's terrible for DNA preservation. It's also super porous so microbes can get into those pores and they'll just chew up the DNA that's in there and that is also terrible for DNA preservation. The oldest DNA that has been recovered so far is from mammoth bones that were preserved in Siberia, in permafrost, frozen dirt. So, the bones were defleshed probably by predators and then buried and then frozen solid and they are probably around one to two million years old which is really old. Most of the DNA we have dates to within the last 50,000 years or so. There's actually DNA that's been isolated from dirt, directly from sediment from Greenland-

HAKEEM (10:03):

Yeah, I saw that, yeah.

BETH (10:03):

... from a place called Copenhagen which is potentially slightly older, Pliocene in age, just before the ice ages started. It's really hard to know exactly how old things are around that time point but that could be the oldest DNA. Still, dinosaurs have been extinct for more than 66 million years and so we do not have DNA that is that old. So, in Jurassic Park, they got dinosaur DNA, which isn't possible, out of amber, which doesn't have DNA, and they pieced it together and then they saw that there were holes in this, not surprising, giant holes as in none of it was real but we're going here because this is the thing, it's a movie. All right. So, these things were there and then they thought there are holes in DNA, I'm going to use frog DNA to fill in those gaps which was a weird choice even then because we already knew that birds are dinosaurs but, whatever, frogs shoved in the middle and that meant that somehow they turned into girls. Is that what happened? I can't really remember the beginning.

HAKEEM (11:03):

Something like that, yeah, yes.

BETH (11:06):

Anyway, yeah. So, set it up, this is how it had to happen. So, now, when people imagine what we're doing, they're thinking, oh, you're going out, you're getting these DNA sequences directly from these bones and you're somehow holding onto them maybe with a really tiny pipetter and then you have another one with another tiny pipetter and you're super gluing those things together and you still can't do it. And it's not going to work, the DNA is broken in a way and it's also really hard. We actually have a much easier way to be successful doing de-extinction. Think about the mammoth project, for example. We know that mammoths and Asian elephants, that's their closest living relative. Hey, fun fact, mammoths and Asian elephants are more closely related to each other than Asian elephants and African elephants are related to each other.

HAKEEM (11:57):

Whoa.

BETH (11:57):

All right. So, we have mammoths and Asian elephants that are only about five million years diverged from each other, that means that they share a lot of their DNA. In fact, they share more than 99% of the DNA sequence between them, they're identical to each other, somewhere around 99.5%, depending on how you count. Which means, if you want to change an Asian elephant into a mammoth, that is a lot easier of a task than piecing together a mammoth by taking little, tiny fragments of DNA with little tiny tweezers and shoving them together which is also impossible. So, now you have this great, great shortcut that you can use where you can start with Asian elephant cells growing in a dish in a lab and you can use the tools of genome editing. The most famous one that most people have heard about now is CRISPR because it allows us some really nice precision to be able to make these changes.

(12:53):

And then, if you can think about it like this, gradually go in and cut out the version of the elephant DNA and paste in its place the mammoth version. So, we're cutting and pasting our way to a mammoth starting with this template that is already 99.5% mammoth. So, that is way easier than piecing it together.

HAKEEM (13:17):

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(14:04):

So, here's a question now. So, is this DNA manipulation happening outside the context of a cellular nucleus? It's free floating in some medium?

BETH (14:18):

No, it is happening in the nucleus of living cells that are growing in media, in a dish in a lab, yes.

HAKEEM (14:24):

Okay, I see.

BETH (14:25):

But we've missed a really important part that you actually highlighted earlier which is how do we know what to change. Being 99.5% the same is great but that 0.5% difference is still a lot of genetic differences between a mammoth and an Asian elephant. And we can't make hundreds of millions or tens of millions or even millions of changes right now, the technology isn't there yet. It will get there eventually but we're not there yet.

HAKEEM (14:53):

So, you're limiting the number of changes you can make.

BETH (14:54):

We're limited. And at Colossal, we're really trying to push the limit of that. How many edits can we make simultaneously, can we cut and paste large pieces of DNA maybe even to the scale of whole chromosome arms at some point so we can make lots of changes at the same time. Because, every time we go into that nucleus of the cell with the machinery that we need to make the edits, we stress that cell out and the cell has to be able to recover after that before it can do something else. So, we have to focus on keeping cells healthy, on maximizing the number of changes we can make at the same time so that the number of times we stress out the cell can be really limited. So, these are all the technologies that we're pushing forward here. And, I like to point this out, as we make these changes, as we figure out how to do multiplex genome editing which is just making lots of changes at the same time or replacing whole genes, these are technologies that can be immediately applied to human health, to animal health.

(15:54):

Once we figure out how we can edit birds and pass those DNA changes down between generations of birds, we could do things like modified genomes in Hawaiian honey creepers so that they can be resistant, resilient to avian malaria so that these species may not become extinct. These technologies are critical tools in what should be an advanced toolkit for biodiversity preservation and those tools are being developed right now on the path to a mammoth and a dodo and a moa and a thylacine. And to me it's such an exciting environment to be part of but we still haven't gotten to a very hard thing that you pointed out at the beginning which was how do I know what to change and that is where these ancient genomes come in handy.

(16:41):

So, we can go out into Siberia and we can collect hundreds, thousands of mammoth bones and extract DNA from them and piece together, using these tiny fragments and computers, sequences of mammoth genomes and we can compare all of these to each other and compare them to elephant genomes and ask where are all the mammoth genomes the same as each other but different from elephants. Because if they're the same as each other, then that means that they're probably important to making them a mammoth. You and I, for example, share a lot of our genomes, 99.9 blah, blah, blah, blah, blah percent because we're both anatomically modern humans. We're pretty much identical genetically, right?

HAKEEM (17:23):

Yeah, yeah.

BETH (17:24):

But you could compare our genomes to Neanderthals and to Denisovins, the other archaic homonin that's our cousin that has a genome sequence that's been ... And you could ask where are we the same as each other and different from them and that will start to narrow it down what it is that makes all of us, what it is that makes anatomically modern humans distinct as a lineage.

(17:51):

One thing we can also do there that's very useful for us is we can look at where you are different from me and where we are different from anybody else that we encounter and we can say those aren't important changes to being a human because they're not shared by all humans so we can throw those out. That is important because that means we can throw out a whole bunch of places in the genome where the mammoths are all different from each other because those aren't things we have to change, we know that they're not important to making a mammoth a mammoth.

HAKEEM (18:20):

When you start thinking of a species to de-extinct, are there certain criteria? Is any extinct species capable of being de-extincted or is it a matter of particular characteristics of that species, particular states of our technology as they interface or even ... I imagine DNA quality and quantity impact somehow what you can do.

BETH (18:43):

Yes, and this is a really important point. I think, eventually, it will be possible to de-extinct or to resurrect some phenotypes or traits associated with any species but there are definitely hurdles that span the gamut and you bring up many of them there. From a social perspective, regulatory perspective, technical perspective, ecological perspective, every species that is a candidate for de-extinction will face a different suite of technical challenges, ethical challenges, ecological challenges across the board.

(19:21):

For example, one of my favorite species to think about is the Steller’s sea cow, this was a ship sized manatee that lived off the coast of California all the way around the Alaskan Aleutian Islands and into Siberia. They became extinct within just a few decades of Western people first discovering them because they would feed a crew of 30 dudes for 30 days because they were so giant and they were really docile just like manatees and dugongs are today. They lived in the kelp forests that were around that area and probably were doomed to extinction even if we hadn't overhunted them because we overhunted the fur seals which were controlling the urchins that were also ...

(20:14):

So, this is a really complicated, really beautiful cascading ecosystem that has to do with otters and fur seals and urchins and these kelp forests and, once you get rid of otters that are eating the urchins, the urchin population explodes and they eat all of the kelp forest and, without the kelp forest, the Steller’s sea cow wouldn't have been able to survive because they hid in and lived in that land. But before we had a chance for that ecological cascade to destroy them, we hunted them to death. Now, would we like to bring them back? I think it would be a really brilliant thing to bring them back. However, there's a problem. Their closest living relative is the dugong which is much smaller, lives off the coast of Australia and, if the same ratio of the size of the mom to the size of a newborn baby were to hold, then, if we used a dugong as a surrogate mom to de-extinct the Steller’s sea cow, the newborn baby would be slightly larger than its mom which probably wouldn't work.

HAKEEM (21:17):

Here's the thing I saw in recent years is there was either a sheep or a goat that was grown in a bag.

BETH (21:23):

Yes, yeah. So, this is really fascinating research and it's grown in a bag but not throughout the entire duration of the pregnancy. So, right now, we can do the very earliest stages and we can do the very latest stages but the middle parts of pregnancy can't be done outside of an actual ... Of a mammal, can't be done outside of a mom, a surrogate mom. We do have a team here at Colossal who is working on a fully exogenous artificial womb starting, of course, with something much smaller, starting on mice and dunnarts, which is a marsupial mouse, a little tiny carnivorous marsupial, to see if we can develop the technology to take them all the way from fertilization to birth. The goal of that team is to eventually be able to do this for elephants and for mammoths so that we can have a fully exogenous artificial scenario that we could use for our mammoth de-extinction project. But this is going to be some time off so our first mammoths will have to be born from an elephant surrogate.

HAKEEM (22:30):

Oh, my God.

BETH (22:30):

But this is a really important stop.

HAKEEM (22:32):

Can you define some time off because my ... Talk about science fiction. Are we talking a decade or-

BETH (22:40):

This is a really great project though.

HAKEEM (22:41):

... a century? What-

BETH (22:43):

Oh, no. For a mouse, I think we'll get to a mouse within the next year or so and that's the first step. The one thing that's really interesting that I didn't know until I started working with this team is that there are multiple different styles of placenta even within mammals-

HAKEEM (22:57):

Really? Wow.

BETH (22:57):

... and all of these have really different needs. And so, there will be different pathways that we take for these different placental types. Who knew? Biology is amazing and confusing and really hard.

HAKEEM (23:07):

So, what you said just addressed the next question I was going to ask you is why do you have to match the species? Why can't you put the giant sea cow inside of a blue whale?

BETH (23:18):

Oh, a blue whale, that would be an interesting idea. Yeah. Well, there are a lot of reasons and they're mostly biological which means mostly we don't understand them. One of the really hard things about even conservation work is to use a surrogate host and they call it intraspecies surrogacy or interspecies surrogacy. So, if we use the same species as a surrogate, we often have better outcomes than if we use different species.

HAKEEM (23:44):

Ah, I see.

BETH (23:45):

And even for species that are relatively closely related to each other and is just one of the complicated things about speciation and how does this happen and what does it mean that, suddenly, two lineages that were the same that could interbreed, suddenly, at some point in evolutionary time, some change has happened which means they can no longer interbreed. Bison and cattle are a great example of this. We know that they diverged only around a million or so years ago, that's not very long ago in terms of how long ago species shared a common ancestor or were the same thing and yet it is very difficult to make hybrid crosses of bison and cattle and this is something that people have tried desperately to do since the beginning of the 20th century.

(24:34):

There were people working in agriculture at the turn of the 20th century who wanted to make cattle that could be as hardy as North American bison and, therefore, live in pasture land, grazing land in the middle of North America during really cold, cold winters. And so, they thought this is a great idea, we'll just breed them together and we'll make a mixture and that mixture, that hybrid animal will definitely be able to survive but also they'll be chill enough for us to be able to deal with them because bison aren't particularly chill but, cattle, they're bred to be chill.

HAKEEM (25:08):

Right, right.

BETH (25:09):

So, we wanted hardy bison but chill cattle and so they decided to make hybrids and it just rarely worked, just absolutely ...

HAKEEM (25:17):

Wow.

BETH (25:17):

Most of the time, it didn't work. If there was an animal that was born, they often weren't fertile or they weren't very fit. I'm just showing that these two species are at the edge of being able to reproduce. Some things had happened in the course of their separate evolutionary history that made them not able to reproduce. But then there are things like brown bears and polar bears, they can readily reproduce and make hybrid offspring. Humans and Neanderthals, we know that they readily interbred and made hybrid offspring. So, evolution is interesting but it also makes our lives hard and so there's a lot of learning that goes into this.

(25:54):

But, actually, that's one of the really brilliant things about working in Colossal, in this space of de-extinction is that we are learning things about biology, we're developing tools, we're developing computational pipelines that we can directly apply to living species, to apply these new technologies so that they don't become extinct and I love that part of our mission, it's really what motivates me day to day.

HAKEEM (26:21):

Wonderful, wonderful. So, it sounds like what you're learning here can result in understanding general principles. So, what do those numbers look like today for the best you can do in terms of ... So, for every time I attempt to bring back or take a embryo and implant it into a womb, what percentage of those tend to be viable and birthed? And then, if it's something that results from a manipulation of sorts, what percentage of those are fit enough to live to adulthood and then what of those are fit enough to reproduce or are we too early to have good statistics on that [inaudible 00:27:05]?

BETH (27:05):

Yeah, this is a really great question and it's something that we're really going to need to figure out. What's difficult about that question is that this hasn't been done a lot. A lot of the data that we have comes from mouse models, in which case, the ultimate goal is not always necessarily to have healthy animals but instead just to see the consequences of a genetic manipulation and so that's not the path that we would be taking and so you can't really take those numbers and fit them directly into what we're doing. What our path does is it really tries to maximize the potential that, when the animals are born, they're going to be healthy and they're going to have the edits, the phenotypes that we're driving and you could see this in our dire wolf work.

(27:53):

So, we had so many different QC steps, quality control steps along the path to do this. We wouldn't ... In mouse work, for example, maybe you don't sequence all of the embryos that you go to and plant because it doesn't matter, there's a really high throughput and it doesn't really matter. For us, we were absolutely focused on animal health, animal welfare and de-extinction and so we spent a lot of time really carefully looking at everything we possibly could with what we had done. We scanned the literature to understand what the potential impacts of the edits that we wanted to make might be and, with any risk profile, we would throw them out and move on to something else. We were deeply sequencing the cell lines throughout the process of first isolating them from blood. So, we isolated cells from a blood draw and we were able to characterize the health of those cell lines and, if they don't look healthy ... Because, normally, what happens in culture is cells, because they're dividing really rapidly, they sometimes lose chromosomes or lose parts of chromosomes and this is just completely normal, it happens all the time in cell culture across the board.

(29:02):

But, of course, we want to make sure that, if we're using a cell to make an animal, it's a healthy cell so we have to sequence them and look at them every time they divide, not every time, but almost every time they divide. And then when we have animals or not animals yet but a fertilized cell, we want to make sure that that cell is very healthy so we sequence that and make sure that there are only the edits that we want to make and no other edits and that, as the cell has been dividing, other strange things haven't arisen. So, we had a very high success rate, pretty much on par with other success rates but it's partly because we were so very adamant about making sure that we were putting the healthiest cell lines through, that the decisions that we were making had the highest chance of leading to healthy animals at the end.

(29:49):

And, obviously, Romulus, Remus and Khaleesi are healthy animals that are thriving and doing well and we can see that they have these traits, these phenotypes that we intended them to have and that we were able to drive using genome engineering.

HAKEEM (30:05):

There are certain things that you can see where the pushback is going to come from before you even take on the work, right, and it's not for everybody. What gives you the courage to step into this arena and do what you're doing?

BETH (30:24):

That's a great question and it's a question I haven't been asked. I think, for me, the motivation is the future, it's biodiversity, it's the fact that we are in the midst of a biodiversity crisis, an extinction crisis, a crisis of arable land, of our ability to feed the people that are alive on the planet today. And we are doing whatever we can, all the solutions we have at our fingertips we're trying to employ but there are new tools. There are tools of synthetic biology, of genetic rescue, of cloning, of all sorts of exciting new developments that we've come up with, people have invented that we are just on the cusp of being able to use. And I want to step up and say, yes, these things might frighten some people because they're new but we can evaluate risks, we can make informed decisions, we can perform very slow and very careful and very deliberate experiments and we can develop these tools that we can use to make sure that, in the future, this planet is both biodiverse and filled with people and that's what keeps me going.

HAKEEM (31:39):

Now, let me ask you a question because this is a thought that came to my mind some years ago. I might be the first person who have ever had it because it's dumb, I'm going to be honest, all right? But what it gets to is I always try to draw a line between what I actually know and what I don't know and here's a thought I had. I don't know that a planet that is made up of just humans and animals that we eat, utilize is going to result in everything falling apart. I don't really know that that's true but do you, as a scientist in this field, know that that's true, that this loss of biodiversity really will have a horrible outcome?

BETH (32:22):

That's an interesting way of putting it. I don't know, I think we don't fully understand the interconnectedness between organisms in habitats. If we get rid of everything except for domesticated species, do we still have the structure of these ecosystems that they need to be able to survive? Are we forgetting about the stuff that we don't pay attention to? And I think, yes, obviously, we do not fully understand how animals and plants and microorganisms in an ecosystem are connected with each other, how they rely on each other, the ecological services that they provide but we know that these things are foundationally important. And as we start pulling them apart, it's like a Jenga game, we can take so many of these pieces out but, eventually, everything crumbles and I don't want to get to that spot.

HAKEEM (33:11):

Yeah, yeah. It would be the equivalent of living on a star ship, right?

BETH (33:18):

Yeah. If we could have teleportation and also one of those devices that makes whatever we want to eat, that'd be cool though, [inaudible 00:33:23], yeah.

HAKEEM (33:24):

Right, right. Right, right. So, as I've studied ancient life after a major extinction, how mammals took over the niches that were no longer occupied by dinosaur species. So, the question I have is is there some part of conservation science where you can actually take an ecosystem and examine it and recognize where there are species missing in the niche and then say, "Okay, here's what we need to do to fill that niche?" Because another element that I think might interfere is the fact that a lot of these animals and plants will evolve together, simultaneously so they become really specialized with each other. So, is there some element of that niche engineering or first niche evaluation then engineering?

BETH (34:20):

Absolutely, and I think this is a really important point that is often missed. The dodo project, for example, we've been working with the Mauritian Wildlife Foundation and Durrell's conservation organization and they've been working in Mauritius for a while. Dodos have been extinct for several hundred years, they went extinct within a few decades of people first appearing on Mauritius and they didn't go extinct because people hunted them, which is the most commonly believed reason why they went extinct, but because they couldn't fly and they laid a single egg in a nest on the ground. And when people arrived, they brought things with them, some of them on purpose like cats and pigs and later monkeys and, some of them by accident, rats coming on boats. And those rats and cats and pigs made an easy meal of that egg in a nest on the ground and, because they couldn't reproduce, they rapidly became extinct.

HAKEEM (35:14):

Wow.

BETH (35:15):

And so, one of the things that we're trying to do is identify places in Mauritius where we can remove the types of species that led to the extinction in the first place to make it a healthy, safe place for these animals to go back. And there has been an incredible amount of work done already in Mauritius to this end and one of the really important projects that they've been involved with speaks exactly to what you're saying. At the same time as dodos became extinct, they lost an endemic giant tortoise and they decided many years ago to reintroduce giant tortoises to some of these places where they're trying to re-establish habitat and remove some of these invasive rodents in particular. And they brought giant tortoises from Seychelles, translocated giant tortoises and they saw that these tortoises are doing really well but also these cascading benefits that they hadn't predicted that are there because of, as you say, these interactions between plants and animals in an ecosystem.

(36:21):

A lot of plant species had established in these parts that weren't from Mauritius but, when these tortoises were put back on the land, those plants had not evolved alongside tortoises and they did not have any mechanism to avoid being eaten by tortoises when they were little baby plants-

HAKEEM (36:39):

Interesting.

BETH (36:39):

... but the native plants did. And so, you put the tortoises back on the landscape and, all of a sudden, the non-native species started getting eaten by the tortoises and you saw those endemic Mauritian plants come back. Even ebony trees, they discovered they grew, they germinated better after passing through the digestive system of a giant tortoise. So, reinstating, re-establishing this missing component of this ecosystem re-established all of these different ecological connections that didn't even imagine were there before they had actually done this. It's really impressive. And it also tells us right back to the beginning how intricately interwoven are components of ecosystems that we don't fully understand. And, to me, this is one of the reasons why we really do have to care about biodiversity loss, not just biodiversity loss of large mammals, but biodiversity loss of every component of these ecosystems right down to the microbes that are in the soils.

HAKEEM (37:40):

Hey, everyone. If you're loving this podcast, please go ahead and like us or leave a comment and also make sure to subscribe so you never miss an episode. Your support means everything and helps us reach more curious minds like yours. Now back to the show.

(37:58):

You mentioned not just the extinction but also modifying the species via this genetic engineering or genetic modification. So, I remember reading somewhere, okay, we have this percentage of ... Non-African humans have a small percentage of Neanderthal DNA.

BETH (38:18):

Well, I want to say this one thing because it's cool and it fascinates me and I'm just going to leave it there as a little tidbit for you because I think you'll find it interesting too. We're all pretty familiar with this idea that everybody out there has somewhere between one and 4% Neanderthal DNA in their genomes. What's less well understood is that it's a different one to 4%. And if we go around the world and we grab up all of the parts of the Neanderthal genome that exist in one person at any part in the world and we piece them together, our study, which used this thing called an ancestral recombination graph, showed that we could piece together around 93% of the Neanderthal genome, almost all of it

(38:59):

And that's super fascinating because it means that, if we want to know what it is that makes humans different, we have to look in the other 7%. That's the part of the genome that either people don't have because of chance, because of genetic drift, it was lost or because a person living with an anatomically modern human family who had that bit of Neanderthal DNA could not survive as an anatomically modern human. That is the part of the genome that we need to find if we want to know what it is that makes humans distinct.

(39:33):

We'd also know that there are some parts, some DNA that we inherited from Neanderthals that have gone to higher frequency than would be expected by chance in human populations and the only way that that can happen is if there is some benefit. We inherit DNA, either by chance, mutation or whatever, that makes us more fit and then that DNA, which just means we have more babies, and then that DNA gets passed on to the next generation. For example, the people who live at high altitude, who have the capacity to have the blood flow more easily at high altitude, that is DNA that was inherited from Neanderthals and Denisovans that lived at high altitude and went to high frequency in those populations and that is just a natural way that evolution by natural selection works.

(40:20):

The goal is to learn all of these things that might lead to different phenotypes and to be able then to pick and choose and say, "I want an animal that is resistant to avian malaria. I want an animal that is resistant to plague." The work that's going on with the Black-footed Ferret Project, and this is led by the Smithsonian and Revive and Restore and the San Diego Frozen Zoo, the black-footed ferret was nearly extinct, it's still endangered, it's one of the ... They call it the class of 1966, the first species that were put on the endangered species list when it was first legislated because it was thought to be extinct, it's in trouble today. It's a really successful captive breeding program so they're doing well but we introduced plague into their populations. Plague, the plague, right?

HAKEEM (41:09):

Oh, geez. Right, yeah.

BETH (41:10):

And when they eat a prairie dog, which is what they do, they get plague and they die. So, we can vaccinate them and that thing but that's not a long-term conservation strategy. But their evolutionary cousin, the domestic ferret, evolved alongside plague and is naturally immune. So, the goal of this project is to figure out what it is that makes a domestic ferret naturally immune to plague in their DNA and then use the tools of genome engineering to transfer that genetic resistance to the black-footed ferret. There is an online database of all the DNA sequences that have ever been published, it's called NCBI and there's one in Europe called Ensemble, they exist, they're publicly open, they're searchable but it's not as easy as look up the gene for plague resistance or look up the gene you brought up skin color. There isn't a gene for skin color, there's a family of genes that are distributed all across the genome, otherwise, we would have two skin colored people but we've got this whole range in diversity of skin colors.

HAKEEM (42:09):

But look, what you're doing is you're messing with my words because, when I heard it, they use a word like allele, right?

BETH (42:14):

Right, yes.

HAKEEM (42:14):

And I use the word gene. So, we talk gene, chromosome, allele, us regular folks don't know the difference in these things.

BETH (42:25):

I know. Us people who work in the field don't know the difference. Oh, no, we do kind of know the difference but it's all very confusing. And, yes ... And they're important too. So, sitting back, a gene is just one place in the genome that codes for a particular protein and an allele will be a version of that gene. But with the skin color, it's not even a difference of alleles and there might be lots of different circulating versions of a particular gene but there's also lots of different genes in the genome that contribute to what we think of as skin color or hair color or height. Any trait that we have that isn't A or B is going to be something that's controlled by lots of different genes in the family.

HAKEEM (43:04):

Lots of different, yeah.

BETH (43:04):

So, if you look at people, it's not just people who are my size, I'm 5-foot tall, and your size, I'm assuming by looking at you, you are much taller than 5-foot tall.

HAKEEM (43:14):

Eight-foot, nine.

BETH (43:14):

Eight-foot, nine, wow. There's not just 5-foot tall and 8-foot tall people but there's a whole range of people and you are an outlier.

HAKEEM (43:23):

Ten sigma. All right. So, that's a nerd joke if there ever was one. So, in terms of conservation, in terms of the phrase you use, frozen zoo, I'm aware of this seed bank in the Arctic, there's been a lot of documentaries talking about this where they are preserving seeds. Do we have a similar DNA bank so that we could preserve any species for which we could obtain its DNA?

BETH (43:53):

That is a brilliant and extremely timely question. There are. The very first one of these was in San Diego, it was founded in the 1970s as a way of preserving cells that, potentially, someday in the future, could be used to help species come back. And, in fact, there have been two clones that have been born, two species have been cloned from the cells that are in the frozen zoo in San Diego. One is a Przewalski's horse and the other is a black-footed ferret. There was a black-footed ferret that was cloned after being preserved for almost 40 years in this tissue culture. It's a way of introducing genetic diversity into a population that has been lost because that population was big and became really small and, when it was small, it loses a ton of diversity. And if you have an animal that lived back here in time, they have diversity that's been lost, we can put it back in that population.

HAKEEM (44:43):

interesting.

BETH (44:43):

So, this, we call them biobanks now and there are biobanks that are emerging all across the world and they should have backups because you don't want to lose all your diversity because there's a power outage somewhere and should be able to regrow yourselves and share all these things. And there's been a tremendous push recently, an international push to create more biobanks and to biobank more of the diversity that's out there and I think this is really going to be important as these new tools for conservation come online. Having these resources available to use is going to be fundamentally important in the future so let's collect them now, biobanks.

HAKEEM (45:18):

Let's do it, yeah. So, here's another question. You mentioned synthetic life. So, what about synthetic DNA? Is it the case that maybe we don't even need ... In the future ... This is related to two questions. One is where is this all going? Where is it going generally for the next century? Where is it going as it relates to humans? And in terms of the DNA technologies, could it be the case that, in the future, we could build an entire DNA sequence from, hey, here's what I want it to be and just go and make it happen? So, instead of saving the actual DNA samples, you just save some information about it so now you don't need refrigeration.

BETH (46:01):

Yeah, that's ... Interesting question. And right now the answer is no and that's because biology is complicated in ways that we don't understand yet. When we synthesize DNA, when I talk about synthetic DNA, I'm not really talking about synthetic life, I'm talking about a strand of DNA that we know the sequence of the letters, the As and Cs and Gs and Ts and how they stick together and we can put them together, stitch them together in a lab using a machine. So, we're just making a string of DNA. Now, that string of DNA is not alive, it is not a life form so we can't do it that way.

HAKEEM (46:39):

But it's an information storage.

BETH (46:40):

It's information storage. But what's interesting about cells and also what makes my job hard is that there is more information than just the sequence of those letters. There's information in, they call it epigenetics-

HAKEEM (46:55):

That's right, [inaudible 00:46:55], yeah.

BETH (46:55):

... it's the nicks that are around the letters that tells us where the chromatin, which is what protects the DNA, is open which means you can make genes from here or closed which means you can't make proteins from here and it's different during different parts of development.

HAKEEM (47:09):

Oh, boy.

BETH (47:09):

There's information in the way the chromosomes fold around each other in cells. There's information ... When we talk about developmental biology and surrogacy, there's a lot of information about the timing and nature of gene expression during development that comes from mom rather than from the developing embryo in a mammal. And so, there's so much out there that we don't fully understand that we will understand, we have now the computational power and the sequencing power to get to this and we're beginning to build these cell atlases and developmental biology atlases and large databases of DNA and we have large language models that we can sick on this stuff and say make sense of this because my human brain is too small for that, you know?

HAKEEM (47:52):

Yeah, yeah.

BETH (47:54):

So, we will eventually understand way more than we do right now. But just preserving on a computer somewhere the genome sequence of an animal is not as good as preserving that cell because we can't take that sequence yet and turn that into a cell that has all the magic that we need to make that into an animal or into a plant.

HAKEEM (48:15):

Wow, wow. AI is going to help us. Well ...

BETH (48:20):

It sounds so lame but it is.

HAKEEM (48:24):

Well, that's what we're saying about everything now so that's the ...

BETH (48:27):

I know.

HAKEEM (48:28):

I'm sure I'm not the first person to think about this but we have extinct human cousins. Are we going to bring them back?

BETH (48:37):

This isn't the realm of reality, this is the realm of where is my ethical line and I think Neanderthals are people and you can't bring a person back without getting their consent. There's a whole regulatory framework for doing research on animals compared to doing research on humans and it just doesn't pass that regulatory muster. We do use regulatory framework for all the research that we're doing, we have external independent committees on animal use and care that we consult with for every one of the experiments that we do. Working on a human, you have to get what's called informed consent. So, how do you get informed consent from a Neanderthal to be brought back to life?

HAKEEM (49:20):

Simple. You bring them back to life and ask them.

BETH (49:23):

And if they say no?

HAKEEM (49:25):

That question answers itself. All right, all right.

BETH (49:33):

Wait, there's one other answer because you also said we have dead cousins or all this stuff and are you going to bring back ... And I also get the are you going to bring back bad guys from history kind of thing.

HAKEEM (49:42):

Oh, yeah. No, we wouldn't want to do that.

BETH (49:42):

Wouldn't this be terrible if you do this?

HAKEEM (49:43):

No.

BETH (49:45):

But the thing about it is we are a combination of the letters of our DNA, the As and Cs and Gs and Ts that make up the genes in our genomes and the environments in which we live. And somebody who lived in the past, even if we could bring them back so they were just a clone of who they were in the past wouldn't be that person because the experience, the environment, everything about it from gestation onward would be something different. And, anyway, we all know human clones because identical twins are human clones.

HAKEEM (50:22):

Twins, yeah. Yea

BETH (50:22):

And they're not the same person.

HAKEEM (50:23):

They're not the same.

BETH (50:24):

You have friends who are twins, you can't just replace one for the other when you want to go have a conversation or you want to ... They are different people. And the same would be true even more so for clones of over time.

HAKEEM (50:36):

So, here's another philosophical question regarding ethics. I believe that human intervention isn't necessarily a bad thing. But generally, that whole idea of using technology to intervene in natural processes, what do you think about that? I see building a dam as geoengineering, right?

BETH (51:03):

We have been manipulating life around us since we have existed as a species. We've been manipulating our habitats, geoengineering, since we existed as a species. These new technologies that we have allow us to do this at a different rate, perhaps at a different scale and so it requires more consideration and more thought and more evaluation of risks and rewards but it is an intervention just like other interventions have been in the past. Stewart Brand, when he wrote the foreword of the Whole Earth Catalog, he wrote famously we are as gods so we may as well get good at it and I think there is some truth to that. When we decided that we would pick plants at a particular time and only pick those that had a certain characteristic, we were changing the shape of what things were more likely to survive and get passed on to the next generation.

(52:01):

We think of conservation as standing aside and giving things the space away from humans to be able to survive but that's not what it is. Instead, we decide where things get to live, how many of them get to live, we control access to food, we control predator's access to them. We have extended our control over most living things on this planet and the things that survive and reproduce are the things that are better able to survive and reproduce in a world that has a lot of people. I do say we talk about risks and there are always going to be risks that are associated with technologies that are new, that are not fully understood but we can also try to understand what those risks are and come up with plans for mitigating risks that are there.

(52:51):

We also though need to understand the risk of not allowing ourselves to at least think through, evaluate and consider strongly implementing some of these new technologies whether it's biological engineering, synthetic biology or geoengineering because that decision also carries risk that we sometimes ignore. We sometimes pretend that not doing anything is not making a decision but it is making a decision and we know the consequences of those decisions.

HAKEEM (53:23):

Yeah, yeah, the responsibility of inaction. Dr. Beth Shapiro, your work is fascinating and amazing. You are amazing and fascinating and I just love talking to you. Anytime you want to buy me a beer or a coffee ...

BETH (53:43):

You're on. Beer. I think let's go for beer, yeah.

HAKEEM (53:46):

Let's go for beer.

BETH (53:47):

I'll be in D.C. in a few weeks, let me know where you are and let's do it, yeah.

HAKEEM (53:51):

Perfect, let's do it. I would love that. I'm sorry but I'm just curious to know in and what you're doing is really so amazing.

BETH (53:59):

And I get to ask the questions next time too because I have a lot of questions and turning the tables here would be a little bit of fun for me.

HAKEEM (54:05):

Hey, listen, you got me. Whatever you want, it's yours. Thank you so much for joining Particles of Thought and I know that our listeners are going to love this. Take care.

BETH (54:15):

Thank you for the invitation. Really, this has been great.

HAKEEM (54:17):

Wonderful.

BETH (54:18):

Thank you so much.