Resurrecting a Woolly Mammoth, with Eriona Hysolli, Head of Biological Sciences at Colossal Biosciences

(Intro Narrator at 00:00:03) Hello, my friends. Today, Joel is talking to Eriona, Head of Biological Sciences at Colossal Biosciences, and they discuss how Colossal is working on bringing woolly mammoths back from extinction, the role de-extinction will play in conservation in the future, and the DNA editing and printing technology that's being used for de-extinction efforts. All of this right here, right now on the Modern CTO Podcast.

(Joel Beasley at 00:00:33) Here we go. This is the Modern CTO Podcast. You're resurrecting woolly mammoths. There's no slowing down. I encourage you to speed up.

(Joel Beasley at 00:00:50) How long, Eriona, until I can have a pet woolly mammoth on a leash hanging out at my farm?

(Eriona at 00:00:56) Well, hopefully there won't be pets, right? I mean, I think the reason why we're pursuing this is because we want them to be free and wild and not pets. But we have a six, seven year timeline for our first calves, and that is mostly because of their long gestation time—at least elephant gestation time, which can be up to 22 months.

(Eriona at 00:01:18) They are very, very special creatures, the elephants. Very interesting and very unique and just very loving as well. I'm very fortunate to be working on this project, and our mission is fantastic. Just blessed to be working alongside so many talented individuals to make this happen, hopefully very soon in the near future.

(Joel Beasley at 00:01:38) If you don't have them at the farm or raise them and then put them in the wild, how do you get them into the wild? Do you take them as infants and just throw them in the wild?

(Eriona at 00:01:48) That's an excellent question. To be quite honest, I think my day-to-day duties involve science at the molecular level, and so I feel like I would leave that aspect of our project and mission down the line, especially in a few years' time, to experts. I am by no means an expert in that area. I would say at the beginning it makes sense for them to be nurtured by other elephants in partnerships like zoos.

(Eriona at 00:02:14) But once we have a sustainable population, I think it makes sense to think about how to actively release them in habitats where they would survive and thrive. At least scaling up will take a little bit more time. As I said, I'm mostly concerned with basic research and the scientific, the molecular biology side and genetic side of it, and then we will leave all the great animal husbandry and animal work to experts who will be better adapted to look after the well-being of our calves.

(Joel Beasley at 00:02:43) I'm curious about the—my wife's pregnant right now—and I'm curious, how do you incubate, I guess that'd be the word? How do you incubate the specimen, the mammoth, so it can grow for those—did you say 20, 22 months or something?

(Eriona at 00:02:58) Yeah, the gestation is 22 months for elephants. Yes. Yeah, it's an excellent question. I think on the short-term goal, we'll still explore some of the more classical approaches such as somatic cell nuclear transfer with a surrogacy option. However, that is not something that we want to pursue long-term. In fact, that is why I'm very excited and passionate about pursuing ex utero development for the Arctic elephants. That means, how can we achieve the full gestation from conception to birth outside of the surrogates? And I think that is essential, especially when we talk about Colossal's efforts in the light of conservation, because you don't want to burden already endangered species with birthing calves when they're already under pressure from a lot of factors that threaten their existence.

(Eriona at 00:03:47) And so those are some of our more long-term goals, which we have, of course, begun to address and begun work on, and we're very, very excited about those. I'm personally very excited about being able to provide whether it's a device, a bio bag, an ex utero approach to gestation.

(Joel Beasley at 00:04:06) Are there currently ex utero applications? Is that something that exists in life today? Can we grow anything ex utero?

(Eriona at 00:04:14) Yeah, there's been some interesting work done. I can highlight one from a Pennsylvania group which did late-term gestation of lambs in what's called a bio bag. And so that was quite exciting work. They were, of course, interested in potential applications for premature babies.

(Eriona at 00:04:31) We are, of course, interested in conservation of endangered animals and how we can scale up numbers so you can just take multiple individuals at the same time, multiple embryos, and later on, fetuses at the same time, while not burdening the surrogate. And so what it would look like—I don't think I can talk more about it at this point—but definitely, it will be some sort of device or bio bag-like structure that could contain or sustain the embryo at full gestation.

(Joel Beasley at 00:05:01) That's awesome. Yeah, it seems like there's several different options, and then that's what we do. We science stuff. We just test the different options, see what works. And you said Arctic elephants. Is that another word for woolly mammoth, or is that something different?

(Eriona at 00:05:14) I think our approaches are still the more immediate work versus a little bit more long-term work. And for the immediate work, I think the changes that we will be implementing on an elephant background to make them adaptable to cold environments would be sufficient to call this organism an Arctic elephant. It's essentially an elephant that has adaptations to a colder climate. So we think of them as sort of lighter versions, like version 1.0 and more later on.

(Eriona at 00:05:40) So at the beginning, I think it's a more accurate way to describe our work as being able to generate an Arctic elephant.

(Joel Beasley at 00:05:48) Okay, so Arctic elephant, then woolly mammoth.

(Eriona at 00:05:51) Yeah, with all the phenotypes of a woolly mammoth.

(Joel Beasley at 00:05:53) Okay, nice. Why this? Why not a dodo bird? Why choose this sort of prehistoric creature?

(Eriona at 00:06:00) That's an excellent question. Colossal is a de-extinction company, so we are actually interested in other species as well down the line. But we're going to take it one thing at a time, of course. To be able to do de-extinction is by no means a very easy path, right? There are challenges associated with it. But for the woolly mammoth, for multiple reasons, I think the most important is that all the extant elephant species are endangered. And therefore, conferring some sort of cold adaptation that allows them to survive in a habitat that's mostly unpopulated and away from human-animal encroachment could be a benefit to the endangered elephant population. And so we believe that de-extinction is essentially conservation with a twist, right? It's a parallel path to saving the elephants.

(Eriona at 00:06:46) The other reason is because we have a lot of specimens that are trapped in the permafrost, both in North America and in Siberia. The spread of the woolly mammoth during the Pleistocene and early Holocene was quite extensive. And so we have a lot of specimens that are trapped in the permafrost, so we have access to a lot of sequences of DNA, some of them that have already been—the genomes that have already been sequenced—and some of them that Colossal as well as other scientists are actually going to generate over time. So, you know, in addition to having the genome of one individual, we have sort of a population-based genomic overview of the species itself and across time as well, because we have older woolly mammoths and newer woolly mammoths.

(Eriona at 00:07:28) So we get to know a little bit about their evolution as well. So we have just this treasure of specimens that we can research and we will know the genomic sequences of. And so that helps when you're doing de-extinction efforts because you understand the genotype-phenotype relationships better. And then you can also—when we're talking about herds in the future, so you want enough genetic biodiversity in the population for them to thrive and survive without the intervention of man. In addition to the aforementioned reasons, also the aspect of climate change effects.

(Eriona at 00:08:02) So we believe that—and other scientists have done great work on looking at the mammoth steppe ecosystem as a very, very biodiverse and rich ecosystem—and the woolly mammoth being an iconic species from that era meant that it sustained quite a biodiverse ecosystem. And with the loss of the woolly mammoth, the whole ecosystem changed, and it's quite poor. There are not that many animals. At least I've been able to travel to Siberia, so I've seen it firsthand that there are not that many animals in Siberia currently.

(Eriona at 00:08:32) The habitats and the ecosystem has changed a bit. It's turned from grassland, which was quite prominent in the ecosystem, to shrubs and coniferous trees. So with the warming of the climate, there's a lot of organic mass that's trapped in the permafrost that's being released in the form of greenhouse gases in the atmosphere. So mitigating some of the climate effects—and so we believe that with the restoration of a healthy, biodiverse ecosystem like the mammoth steppe ecosystem, with the woolly mammoth being the iconic species, we believe that we can restore the health of the ecosystem. And potentially this restoration—the fauna and flora of that particular ecosystem—will kind of act like a sponge, keeping the organic matter that's trapped in the permafrost recycled rather than being released in the atmosphere.

(Eriona at 00:09:20) So for a lot of reasons, we believe that the woolly mammoth is a great species to go after for de-extinction and conservation efforts in a thoughtful, ethical manner. But again, by no means are we interested only in that one. Of course, down the line, we'll be interested in selecting other species for de-extinction.

(Joel Beasley at 00:09:40) Who doesn't love the woolly mammoth?

(Eriona at 00:09:42) It's so bizarre, the woolly mammoth. It's very cuddly. I believe it's cuddly from the looks of it. We'll find out.

(Joel Beasley at 00:09:49) We will. I was reading on the website something about like 30,000 species a year are going extinct. And when I saw that, I thought, okay, that's pretty crazy. That's a lot. But don't new species come to? And so I did a basic Google search—so you feel free to correct me—but then they said something along the lines of like 46 new species an hour. It was less than the 30,000 for sure. I think it was like 11 or 18,000 a year are created or found or discovered, but that still leaves a net negative, right? Is that information correct, or am I interpreting that wrong?

(Eriona at 00:10:29) I'll take your word for it. I'll probably have to double-check, so in this case I'll just take your word for it. But I think my thoughts would be that what Colossal is doing is providing a parallel path to conservation in case we want to bring back species that are iconic and that are needed for healthy ecosystems. And the woolly mammoth, you know, fits the description, right? I think restoration of the woolly mammoth and healthy, thriving populations of woolly mammoth—Arctic elephants initially—would provide many, many benefits, not just restoration of the ecosystem itself, but as I mentioned, climate change and also climate change benefits as well, or mitigation of. And also trying to save the extant elephant populations. But I think, yes, while there are new species that emerge, every time there is a species that is lost, it leaves behind a big hole, and it can actually potentially even degrade the ecosystem altogether. And that's actually what happened with the mammoth steppe ecosystem. The loss of the woolly mammoth, or the absence of the woolly mammoth from that ecosystem, is associated with a dearth of biodiversity.

(Eriona at 00:11:39) And so we can all agree that healthy, biodiverse ecosystems that thrive are actually beneficial to the planet as a whole, but even to us as a species, because we learn so much from the animals and other species that populate Earth. For example, on the elephant front, we know that they have multiple copies of this TP53 gene that makes organisms somewhat resistant to cancer, and they're known to have reduced cancer rates compared to other longer-living species. So that's just one of the things that you learn from studying the genomes of existing species and preserving this biodiversity for their sake and for our sake. I think everyone can agree that it's a very noble cause.

(Joel Beasley at 00:12:22) Oh yeah, for sure. I'm on team—I'm on your team. We're on the same team. I'm just curious. And I was sort of setting the tone for this next conversation I want to have about we're losing species—30,000 a year—we're gaining them at some number per year. When I think about saving species that are going out, like an elephant, I'm all about it, right? I'm like, oh, those are beautiful creatures. I love them. That's cool. Let's save an elephant. But when I think about making a new one, I feel like that would be like a lot of ethical issues, and people would really not like that. They would say you're playing God or something. You know, they wouldn't like us tinkering and making new ones. Nature is making thousands of new ones just autonomously right now. Have you ever thought about, can this technology in the future somehow lend itself to creating new ones?

(Eriona at 00:13:20) Yeah. I mean, in a way, if you think about it, the Arctic elephant is a little bit of a mix of two different species, right? But I have to say that I think when people mention scientists playing God, I mean, there are of course all these criticisms, but at the same time, humans have done this a little bit ever since we've evolved bigger brains. And I think that you can sort of just look at one of the more common instances. This is through the many breeds of dogs we have. I mean, that's man-made, essentially. And crops—selective breeding of a lot of plants. We've done that, not nature. And so I think there are a lot of instances where human intervention has led to a lot of benefits for society.

(Eriona at 00:13:59) You know, thinking of novel ways for conservation also, I think—I believe strongly that it's a beneficial thing for society. Now on the ethics, absolutely. I mean, we do that as well. We actually have people on our scientific advisory board who very strongly think about the ethics of what we're doing. I think actually we believe very strongly in radical transparency of our work. We could have done this hidden without anyone knowing, but we want to engage the public and we want to hear what they have to say, their feedback, because that really matters. And we want to also change minds. We also want to show that it is one way to do it. Is it the only way to do it for a lot of species? I think it's a case-by-case consideration. In the case of the elephants, they're quite large and quite trackable, I would say.

(Eriona at 00:14:45) And so the benefits definitely outweigh the cons in this case. So yeah, personally, I view our efforts as very radically transparent. Everything is for people to see. I mean, we have a quite extensive website with a lot of information, and we're very open. We're of course very active on social media as well, where people can reach us and ask questions to us directly.

(Eriona at 00:15:09) But also, as I said, it's a case-by-case consideration for whether to bring or to save a species or not, depending on whether you even have a habitat or an ecosystem that can sustain their growth and their survival. And in the case of the woolly mammoth, Arctic elephants, it's still very much—while it's changed a little bit, it hasn't changed radically for it not to sustain a return of the woolly mammoth, right? So you need to have the ecosystem, or you need to have the habitat to sustain that species. Modern medicine has saved a lot of people as well. So advanced, transparent progress and technologies have saved lives, and we just believe that we can apply a lot of those technologies to saving animals as well. And a lot of what we will build for the pipeline of de-extinction and conservation can also, in return, be used for species such as ourselves for health and disease, because much of the genome engineering tools that are used for mammalian editing are the same. With some tweaking, they're the same. So a lot of the tools we will build can also very easily apply to applications for human health and disease. So it's kind of like a circle.

(Eriona at 00:16:15) Right? We use the technologies that are built for humans and other species for, in this case, Arctic elephants, but also more tools that we built can benefit other animals, and that includes also humans as well.

(Joel Beasley at 00:16:28) Have you seen Jurassic Park?

(Eriona at 00:16:30) I have. I know that we get a lot of that comparison.

(Joel Beasley at 00:16:34) So I was just, so here's the follow-up question.

(Eriona at 00:16:37) Mm-hmm.

(Joel Beasley at 00:16:38) Is an emphasis on transparency partly due to the bad things that happen when you're not transparent in Jurassic Park?

(Eriona at 00:16:45) I think transparency is... I have to say that as a scientist, we sometimes do get this criticism of us not being transparent with our work, regardless of whether it is de-extinction or some other work. Right? So we have a reputation for—I think a lot of the public may have perception that we're doing crazy things behind closed doors. But I think for challenging, ambitious, pioneering, and also boundary-pushing projects, it's even more important to actually be very open with the public as to why we're doing this. In fact, I think we get a lot of encouragement from the public.

(Eriona at 00:17:18) Right? I think a lot of people are interested in saving species. And while we believe that this is a parallel approach to some of the traditional conservation efforts, conservation efforts, at least the traditional ones, have worked only minimally so far. Right? So there is that urgency to try to innovate on that front as well, just like we innovate on a lot of aspects of life. And just putting all your eggs in one basket probably is not the right strategy, even in conservation.

(Eriona at 00:17:45) And with this project in particular, I think since a lot of people ask whether, you know, we should do this, I think we're even more engaged with the public as to why we are doing this, why it's a good thing. I mean, there's a lot of species that are in dire need of help, and I think this is an innovative way to do so, taking advantage of a lot of the progress that's happening in synthetic biology and genome engineering.

(Joel Beasley at 00:18:10) The business side of things is, like, how do you get funding to do this? What's the commercialization ultimately?

(Eriona at 00:18:18) Another aspect that I feel like I can claim my limitations is actually the business side. As a scientist, I'm not that concerned at all about that aspect. The cool thing about our investors and about our leadership is that they want us to focus on the science, and I'm very passionate about focusing on the science. The business side of it does not affect my work on the day-to-day too much. But I do have to say that, and so I also have to mention that a lot of our investors believe a lot in our project, and they serve like a passion, a hobby, rather than something that they have invested because they want to make money out of it.

(Eriona at 00:18:57) Having said that, I think our company has—of course, we believe that the tools we build as we progress in our goals can be applicable to, as I mentioned, applications outside of de-extinction and conservation. And we can talk about potentially at that stage about licensing or allowing these tools to be used for those applications. So that's one aspect of the business development side.

(Joel Beasley at 00:19:20) I'll write your official answer as exotic animal restaurants.

(Eriona at 00:19:26) No, I'm kidding.

(Joel Beasley at 00:19:28) I'm kidding.

(Eriona at 00:19:28) There'll be no restaurants involved.

(Joel Beasley at 00:19:31) I know. Right? I talked to this one scientist who was cloning salmon. So he took the part of the salmon you would eat, and he figured out how to clone those cells so you can grow salmon in the lab. And I thought that was absolutely fascinating.

(Eriona at 00:19:49) Yeah. I mean, I think I'm actually very interested in the great work that's happening across a lot of labs and companies. Currently, I'm vegetarian myself, so I'm always interested in more interesting food options. I'm a fan of plants, but, you know, sometimes you want to look beyond what's for dinner other than plants. Right?

(Eriona at 00:20:08) And so growing meat in a lab, in a dish, is actually quite exciting, precisely for the reasons you mentioned, which is you don't have to go back and kill animals. You can just grow them starting with a cell line. So there's some very cool engineering that is happening in that aspect. I'm personally very interested in that. But, yes, our efforts don't involve any of that work.

(Joel Beasley at 00:20:32) Can you walk me through from a high level the way you get from, okay, we're gonna make this Arctic elephant, to actually having the Arctic elephant? Do you immediately run into a lab and just start mixing liquids together? Like, how do you get from idea to reality?

(Eriona at 00:20:53) Great question. So I think for us, we start with cells from elephants, and we employ multiple genome editing techniques. We work in collaboration with George Church's laboratory. So Colossal also licenses a lot of technologies from George Church's lab. So we employ some of these genome editing technologies, most prominently CRISPR-based technologies.

(Eriona at 00:21:17) Mm-hmm. And we make precise edits on the loci that previously in our comparative studies between species, proboscidean species such as the mammoths and the elephants. So backtracking a little bit, you have to start with the genomic sequences, and that's what we start with, multiple genomic sequences for extant elephants and the woolly mammoths. And then you'll run a comparative study looking at the regions of the DNA where they're different from each other. And then you further narrow down, of course, because there are still quite a few of them, further narrow down to areas that could have implications for phenotype.

(Eriona at 00:21:51) So something a genetic change that is associated with a trait, and we're interested in cold adaptation traits. And then you implement those changes using gene editing tools such as CRISPR-based tools. Following that, you grow the cells. You can differentiate cells into different lineages so that you can actually try to assess whether you're getting the trait that you're expecting for the genetic change. And then further down, as you screen the cells that you desire that have most of the changes that you want to implement from, you know, the set of genes that we have narrowed down from that comparative bioinformatics study.

(Eriona at 00:22:28) Then, of course, the next step after that will be some of the embryology work associated with nuclear transfer and animal work down the line. But that gene editing and cell engineering and screening stuff can take potentially two years.

(Joel Beasley at 00:22:43) All right. So you get the elephant cells, and then you know what the woolly mammoth or the Arctic elephant looks like over here because you have some sort of prehistoric sample. Right? And then you look at the differences between them, and then you use CRISPR...

(Eriona at 00:22:54) We know what the woolly mammoths look like.

(Joel Beasley at 00:22:56) Yeah. Yeah.

(Eriona at 00:22:57) We know what the elephants look like, and we know what the woolly mammoths look like. And we have genetic information from multiple individuals from each of those species, and then you run the comparative study.

(Joel Beasley at 00:23:07) And then you splice the woolly mammoth over into the elephant.

(Eriona at 00:23:11) So you don't have to splice anything with the emergence of synthetic biology. You can synthesize pieces of DNA. You don't have to port them from a woolly mammoth sample, which is a cool thing about it. All you need to know is the in silico sequence of the genome, and you can actually make any piece of DNA that you desire synthetically. So you can either do that, or you can actually make a precise edit in one single nucleotide with some of the newer CRISPR editing tools.

(Eriona at 00:23:40) So it's a combination of tools. That's the reason I mentioned CRISPR-based tools rather than just one tool.

(Joel Beasley at 00:23:45) Yeah. How do you get the—you've got a sperm and an egg. Right? Is that true for the woolly mammoths?

(Eriona at 00:23:51) In this case, what Colossal is also interested in is driving this pluripotent stem cell-like cells called iPS cells. You know, they revolutionized stem cell biology in human and other species when they were first derived a few years back. The person who invented this technology, Shinya Yamanaka, got the Nobel Prize in Physiology and Medicine. With four transcription factors, a minimum of four transcription factors, you can actually generate or reverse the program of a cell going from a differentiated, fully mature cell to a more pluripotent stem cell-like cell. And from that population, you can derive any other lineage that you desire, including gametes, sperm and egg.

(Eriona at 00:24:28) So, technically, you can start with a cell line from an elephant and derive the sperm and egg from that cell line and never having to go to an elephant to retrieve them.

(Joel Beasley at 00:24:39) Come on now. That's crazy.

(Eriona at 00:24:41) It is an amazing technology, and it's just such a great technique for conservation as well because you can actually get as much biological material like blood, which is easy to access for a lot of endangered species, and bank it. And then in the future, at least for, you know, scientists and researchers that are interested in doing work for that species, they can derive a lot of cell lineages, including gametes, from that banked cell line. So that's very, very exciting work.

(Joel Beasley at 00:25:07) So you can go dig through the permafrost, find some prehistoric animal, sequence its DNA. And then how do you get from the sequencing the data in the computer to actually having the cells?

(Eriona at 00:25:21) Yeah. So a few years back, a few groups were also interested in trying to find an intact, viable cell from this mammoth specimen, given that some of them are very well preserved. I mean, if you look at them, you would think that they just passed just the other day. They're just so fresh-looking. But because of radiation damage and DNA damage sustained across time, also right after the death of an animal, it was quickly shown that DNA is highly fragmented in this specimen no matter how well preserved they are.

(Eriona at 00:25:50) So finding an intact cell is next to impossible. So the cool thing is that synthetic biology and genome engineering progress and revolution, you don't need any of that. You don't need to find an intact cell. You just need enough DNA information to derive the full genomic sequence, which we are able to do routinely from this specimen. So that's what we start with, as I said, that sequence.

(Eriona at 00:26:11) And then you identify the spots where you actually have to make that change. So you compare, of course, you align the elephant sequence to the woolly mammoth sequence, and they are very similar. The closest living relative of the woolly mammoth is the Asian elephant, and they're roughly 99.6% similar. So it's still a lot of changes, but at least it's very manageable because they are so closely related. And so you will look at the spots where they are different from each other, and then you have to integrate the CRISPR-based and other genome editing tools based on the spot.

(Eriona at 00:26:43) You have to change—based on that DNA region, you have to change. So for areas where you have to make more than one change, maybe potentially it could make sense to make that piece of DNA and then swap it into the elephant cells. So you can just synthetically make that piece of DNA. For other regions of the elephant genome, just one of the base editing or prime editing tools on the CRISPR side, you can just make one precise change or several nucleotide changes at a time, and you don't need a piece of synthetic DNA for that. It's just the enzyme that converts one nucleotide to another nucleotide.

(Eriona at 00:27:19) So there are a variety of tools that you can actually use. So we use a combination of tools.

(Joel Beasley at 00:27:24) Okay. So you can take the direct woolly mammoth DNA and just clone it synthetically. Like, you can take it, put it in your computer, and then the computer...

(Eriona at 00:27:32) You only need the in silico sequence. Right? And then you can just input that sequence. You know, a lot of providers can actually do that. They can routinely ship you DNA the next day. Right? You just send them the sequence of what you would want synthesized, and then they'll send you the DNA in this tube format, and you can start with that. So you can manipulate the DNA that you receive that is synthetically made and then input it or swap it into the genome in the cells in your desired cells or targeted cells. In our cases, the elephant cells.

(Joel Beasley at 00:28:04) But if you don't have, like, an elephant, you have to find some other cells. You can't just do it off of synthetic DNA.

(Eriona at 00:28:11) Yes. So interestingly, you can do that. You can actually make a full synthetic genome for prokaryotes. It's been achieved for multiple strains of bacteria. It's fully synthetic, and there's ongoing efforts for the synthetic yeast as well.

(Eriona at 00:28:25) The full synthetic yeast genome, right, and the full synthetic bacterial genome. That's been achieved. The mammalian genome is next. We're not quite there yet, so just making it fully synthetic and rebooting a cell, any cell, is probably in the future. Not something that we're interested in doing, but it is something that, especially, researchers who—and that also includes researchers in George Church's lab who's interested in the next stage from going from sequencing the DNA to writing genomes in this effort called GP-write or Genome Project-write.

(Eriona at 00:28:57) So that's possible, as I said, to do with smaller organisms like bacteria and yeast, and mammalian cells are next because they are much, much larger and more complex. But in this case, because the species are so closely related, you don't have to do that. You don't have to build the genome from scratch. I think it will be actually quite wasteful to do that because the genomes are so similar. So gene editing tools are actually quite sufficient, which is why Colossal believes this is just a matter of scaling up these technologies, not whether it's doable or not, but how multiplexable we can make them.

(Joel Beasley at 00:29:31) I've been following this company for three or four years. They're called Catalog DNA. They read and write DNA data into DNA. And they started to commercialize about a year and a half ago, I think, and I had them on the show to talk about it. I was like, hey, guys. I've been following the work. And I had watched them go from it taking an extremely long time to write a bit of data in DNA to them being able to write several megabytes, I believe, a day in DNA. So they essentially, in three or four years, leaps and bounds pushed this technology forward to be able to write DNA. And when I was asking them about, you know, reading it, they said that technology is advanced for several reasons. Like, it gets advanced, you know, because we need to read our DNA for medical reasons.

(Joel Beasley at 00:30:18) Right? So that's why you would have that technology be more advanced than the writing of DNA technology. Right? And so it seems like what you're doing over at Colossal is in the pursuit of doing this woolly mammoth project, you're having to push forward various different technologies. Is that right?

(Eriona at 00:30:38) Yes. Absolutely. That is more, of course, on the editing side, as I mentioned. Sequencing will—it's progressed quite a bit. I think the person you talk to is absolutely right. It's, the sequencing also has quite a bit of head start, right, compared to the writing. So, of course, they're a bit more advanced there. And it makes sense to read before you write anything. You need to learn a little bit the letters and what's written before you actually start writing and composing. But for us, it's mostly we rely on a lot of technologies that are out there with collaborators and, of course, commercial entities for sequencing because we are interested in sequencing more elephants, sequencing more mammoths.

(Eriona at 00:31:18) The more data we have, the more population-based genomics landscape we can create for the species we're interested in. But we're more interested in multiplexing the editing. Right? So while elephants and woolly mammoths are highly similar to each other, it still translates to a lot of changes, even millions of nucleotides across the genome. So going from making one change at a time to making 1,000 or 10,000 changes at a time is actually what when I was in the Church lab, I was very much interested in that aspect.

(Ariana at 00:31:49) So multiplex gene editing and what we are interested in now at Colossal—you want to be able to make these changes faster, and if you can, all at once. Right? It's still probably we're not there yet to make all the changes that you want at once, but at least increasing the level of multiplexability for the gene editing, and not just one at a time, but multiple at a time, is crucial to our efforts.

(Joel Beasley at 00:32:13) We were talking about yeast. I think you said yeast was one of the simpler ones that's fully synthetic. So does that mean me being a scientist in, you know, New York, I could take this synthetic yeast, make a couple changes to it in the computer system, send that file, that computer system file down to a scientist in Florida who could then just print that out in their lab?

(Ariana at 00:32:34) Print the sequence you mean?

(Joel Beasley at 00:32:35) Or yeah, just like make that yeast in their lab.

(Ariana at 00:32:38) That's the goal of the future, right? To just, if you input a sequence, a full sequence, that you can get all the genome fully assembled. Because I think—so in addition to the synthesis technologies that had to advance to make longer and longer pieces of DNA, the short pieces is fine, but if you really want to scale up and generate longer pieces, it's a bit more challenging. But I think that's also advanced quite a bit recently, and you can actually get it for cheaper and faster.

(Ariana at 00:33:04) It's still not sufficient to show the scale of what any genome, and particularly a mammalian genome, looks like. Right? I think it's three gigs of nucleotide sequence. It's still quite a bit for a general mammalian genome. So yeah, the dream is in the future to be able to just input that sequence, which we have it. We have multiple of them. In the case of humans, we have hundreds and thousands of these genomic sequences around. So being able to input, and then out comes a fully assembled genome. Because the assembly of these short pieces together is actually also a challenging aspect of synthetic biology. So you can do that, as I mentioned, with smaller genomes like bacteria and yeast, but when you go to something like a mammalian genome, it's still a bit more challenging.

(Ariana at 00:33:52) It's still doable, but takes years, or it takes a long time, at least with the current technology. So yeah, I think printing a full genome would be something that we would all be very, very excited to see in the very near future. We're not quite there yet, but we're getting there. I think the Church lab and others have actually generated these synthetic bacterial genomes by assembling pieces of DNA together. And that's more routine now that you can actually achieve it within a couple of years or so.

(Ariana at 00:34:25) For longer DNA, for longer genomes, I think that you would need a little bit more time. But we are heading towards that achievement. I think it's just a matter of time.

(Joel Beasley at 00:34:33) Maybe by next year.

(Ariana at 00:34:35) We do need to—I do have to say it's not as easy as it sounds sometimes because you do need to take the genome back into a cell to reboot it. Given that it's a large piece of DNA, it's not like the cells are very, very happy to intake so much DNA at a time. So it's going to be a fairly inefficient process there. But again, I think starting with the megabase genome is actually already major progress. And so the next step would be—you just have to—it's a lot of iteration. It's just a matter of time.

(Joel Beasley at 00:35:03) So it seems like you like animals a lot.

(Ariana at 00:35:05) I do.

(Joel Beasley at 00:35:06) Is there any particular species that you're most concerned about going extinct right now?

(Ariana at 00:35:11) Elephants. I mean, I'm biased here about elephants for sure. They just have also—so much we can learn so much from them. They have long lifespans. They are resistant to cancer. We don't know much about them. They're a little bit of an outgroup as well among mammals. So we just need to—we want to be able to learn as much from what they're hiding in their genome, their genomic secrets as possible, and they hopefully can also educate us how to save them. But yeah, I'm very, very biased towards elephants.

(Joel Beasley at 00:35:42) For you to get this far, you must have great leadership and organizational abilities. When you look back at where you started when you were 16, when you came here to United States, to where you have gotten today, what sort of habits do you think that you have or traits that have allowed you to have the success that you've had?

(Ariana at 00:36:03) I mean, drive is definitely one of them. Passion for science. A lot of scientists have this, especially biologists. Right? We're just naturally very curious. And sometimes just a little bit of risk taking, which is interesting because scientists don't—we're not all risk takers. Right? But a little bit of risk taking is good. And so actually, I learned that over time a little bit more, especially being in George's lab. You just push the boundaries a bit in terms of what's achievable. Right? I think one of the things that I learned from George is he does mention that some of the projects are just a postdoc lives away. Right? So just a few years away from being completed or being achieved. And you don't know that that's the case when you start, but it can be the case.

(Ariana at 00:36:45) So yeah, just natural curiosity, drive, and also working with great individuals. Right? I think you need to be in the great environment, in a nurturing environment, to satisfy your curiosity. In a way, if you're in an environment where your ideas are shut down, it's a little bit more difficult to pursue them or think seriously about them. And I think if you're in the right environment, you can do great things. And I've been very fortunate with my career trajectory so far, learning all about stem cells during my PhD, learning all about synthetic biology during my postdoc, and now I get a chance to play and use that background and that expertise, play around a little bit in the lab with some of the cool technologies, and of course, apply it to something serious and important like de-extinction conservation.

(Joel Beasley at 00:37:33) Do you get to spend much time in the lab?

(Ariana at 00:37:36) During my PhD as well as during a postdoc, yes. I mean, in a way, we're married to the lab at that stage of training. Right now, it's of course a lot of—we have our team is growing. We have amazing talent. So of course, it's a lot of moving pieces that have to operate smoothly. So I do spend—we do have to confess that I spend a lot of time in meetings now. That also is a derivative of our lab being in two different places as well. We are located in Dallas, and we're located in Boston. So we do need a little bit of coordination there, which is very, very exciting. Yeah.

(Ariana at 00:38:09) And a growing team. So because of that, I did spend a little bit more time in meetings, but I do make sure to block times in my schedule to actually do work in the lab. I'm still very much involved with lab work myself. And recently, in particular, I've been interested in the pluripotent stem cell work for elephants. And so they are, compared to other species, they'll be tricky to derive pluripotent stem cells from. And so we're very focused on that as well because it's just such a crucial—as I mentioned before, it's such a crucial part for conservation to be able to derive these cells that have the potential to become any cell type in the body. So in a way, you don't have to do any animal work because you can actually work with these cell culture models that you can develop into more complex models, either 3D or organoid cultures.

(Joel Beasley at 00:38:58) Yeah. My stepmom and my brother are both doctors, and my stepmom is really into studying the stem cells and how they're using them to help quadriplegic people regain some function.

(Ariana at 00:39:13) Yes. Stem cell potential is immense in so many areas. Cell therapeutics, of course. When I started my training, my doctoral training, actually, researchers had been doing work in embryonic stem cells for a while. At that time, there was also a lot of controversy associated with using embryonic stem cell lines derived from discarded IVF embryos. And then this Japanese group, with Shinya Yamanaka being the leader of that, of those efforts, comes along and just is using only four transcription factors, four genes, to derive the same cell type as what you derive from the discarded embryos, this blastocyst stage of their development. And so that was quite exciting because it revolutionized the whole stem cell field. And given that you can derive any cell lineage from them, you can imagine how much work is going into making blood cells, making neuronal cells from the iPS cells, and it's incredible work. And it can save species as well. Just recently, there was a great paper showing some early development from northern white rhino iPS cells.

(Ariana at 00:40:17) As you know, there are only two northern white rhinos left. And so for all intents and purposes, the species is extinct because they cannot reproduce. And being able to actually bank some of these cells that you can derive pluripotent stem cells from and then be able to actually generate a full organism from these cells is going to be so essential for conservation work.

(Joel Beasley at 00:40:38) Why can't the rhinos—if there's two of them, why can't they reproduce?

(Ariana at 00:40:42) I think they're past their reproduction age, and I think there's been multiple cycles of egg retrieval that have rendered them slightly resistant to more successful egg retrievals. So but there are cells that are banked from northern white rhinos, so there is definitely a lot of hope there. But at least on the natural front, there's only two individuals that no longer produce. So until these iPS stem cell efforts and cloning efforts are successful, the species seems to be extinct.

(Joel Beasley at 00:41:11) So they were trying. They have these two white rhinos left, and they were trying to—

(Ariana at 00:41:16) No. They have—they actually have retrieved eggs, which is—they retrieved eggs. Yeah. Which is—and so they have retrieved eggs in the past, just not—it can no longer be the case. So there are some embryonic stem cells actually that are derived from the northern white rhino. So yeah, so there is hope there. And just at least that currently, there are only two individuals. So by current standards, we can consider them extinct.

(Joel Beasley at 00:41:38) I'd still give it one more shot. I'd put them both in the room, put on some R&B music. This is great. I am so happy there are people like you out there pushing these things forward because it's super, super cool.

(Ariana at 00:41:54) These platforms are crucial. I'm very, very thankful for the invitation and being able to also share a lot of the work we do and our goals through these kind of platforms is absolutely essential. And so I'm very fortunate and very thankful that that's the case here.

(Joel Beasley at 00:42:11) Thank you so much for listening. And if you found this episode useful, please share it with a friend or colleague who you think would get value from it. And if you have topics that you'd like to hear discussed on the podcast, either add me on LinkedIn or send me an email: [email protected]. Every time I get an email or LinkedIn message, it absolutely makes my day and inspires me to keep going.